Pyrazole derivatives and their use as LPAR5 antagonists

ABSTRACT

The present invention relates to compounds of the formula (I), wherein the residues R 1  to R 5 , V, G and M have the meanings indicated in the claims. The compounds of the formula (I) are valuable pharmacologically active compounds for use in the treatment of diverse disorders, for example cardiovascular disorders like thromboembolic diseases or restenoses. The compounds of the invention are effective antagonists of the platelet LPA receptor LPAR5 (GPR92) and can in general be applied in conditions in which an undesired activation of the platelet LPA receptor LPAR5, the mast cell LPA receptor LPAR5 or the microglia cell LPA receptor LPAR5 is present or for the cure or prevention of which an inhibition of the platelet, mast cell or microglia cell LPA receptor LPAR5 is intended. The invention furthermore relates to processes for the preparation of compounds of the formula (I), their use, in particular as active ingredients in medicaments, and pharmaceutical compositions comprising them.

This application is a national stage application under 35 U.S.C. §371 ofInternational Application No. PCT/EP2013/060171, filed May 16, 2013,which claims priority of European Application No. 12305552.7 filed onMay 18, 2012, the disclosure of which is explicitly incorporated byreference herein.

The present invention relates to pyrazole derivatives of the formula I,

wherein the residues R¹ to R⁵, V, G and M have the meanings indicatedbelow. The compounds of the formula I are valuable pharmacologicallyactive compounds for use in the treatment of diverse disorders.Compounds of the formula I exhibit a strong anti-aggregating effect onplatelets and thus an anti-thrombotic effect and are suitable, forexample, for the therapy and prophylaxis of cardiovascular disorderslike thromboembolic diseases or restenoses. In addition, compounds ofthe formula I inhibit LPA-mediated activation of mast cells andmicroglia cells. The compounds of the invention are antagonists of theplatelet LPA receptor LPAR5 (GPR92) and can in general be applied inconditions in which an undesired activation of the platelet LPA receptorLPAR5, the mast cell LPA receptor LPAR5 or the microglia cell LPAreceptor LPAR5 is present or for the cure or prevention of which aninhibition of the platelet, mast cell or microglia cell LPA receptorLPAR5 is intended. The invention furthermore relates to processes forthe preparation of compounds of the formula I, their use, in particularas active ingredients in medicaments, and pharmaceutical compositionscomprising them.

In the industrialized world thrombotic complications are one of themajor causes of death. Examples of conditions associated withpathological thrombus formation include deep vein thrombosis, venous andarterial thromboembolism, thrombophlebitis, coronary and cerebralarterial thrombosis, cerebral embolism, renal embolism, pulmonaryembolism, disseminated intravascular coagulation, transient ischemicattacks, strokes, acute myocardial infarction, unstable angina, chronicstable angina, peripheral vascular disease, preeclampsia/eclampsia, andthrombotic cytopenic purpura. Also during or following invasiveprocedures, including insertion of endovascular devices and protheses,carotid endarterectomy, angioplasty, CABG (coronary artery bypass graft)surgery, vascular graft surgery, and stent placements, thrombotic andrestenotic complications could occur.

Platelet aggregation plays a critical role in these intravascularthrombotic events. Platelets can be activated by mediators released fromcirculating cells and damaged endothelial cells lining the vessel or byexposed subendothelial matrix molecules such as collagen,lysophosphatidic acid or by thrombin, which is formed in the coagulationcascade. Following activation, platelets, which normally circulatefreely in the vasculature, and other cells, accumulate at the site of avessel injury to form a thrombus and recruit more platelets to thedeveloping thrombus. During this process, thrombi can grow to asufficient size to partly or completely block arterial blood vessels. Inveins thrombi can also form in areas of stasis or slow blood flow. Thesevenous thrombi can create emboli that travel through the circulatorysystem, as they easily detach portions of themselves. These travelingemboli can block other vessels, such as pulmonary or coronary arteries,which can result in the above-mentioned pathological outcomes such aspulmonary or coronary embolism. In summary, for venous thrombi,morbidity and mortality arise primarily after embolization or distantblockade of vessels, whereas arterial thrombi cause serious pathologicalconditions by local blockade.

Lysophosphatidic acid (LPA) is an important bioactive phospholipid witha wide range of cellular functions. Levels of LPA are tightly regulatedvia its synthesis, controlled by two different pathways. The firstconsisting of phospholipase D (PLD) and phospholipase A2 (PLA₂)activity, the second consisting of PLA₂ and lysophospholipase D(lysoPLD) activity. The most commonly used LPA in laboratory praxis is18:1 LPA (1-acyl-2-hydroxy-sn-glycero-3-phosphate). However, many otherforms of LPA exist in the organism, with varying length of the fattyacid chain, different saturation grades and coupling of the fatty acidchain to the glycerol backbone, i.e. coupling via an ester or ether bond(Choi et al., Ann Rev Pharmacol Toxicol (2010), 50, 157-186). A keyenzyme for LPA synthesis is autotaxin (ATX), Enpp2 in mice. It has beenshown that ATX has lysoPLD activity and that Enpp2^(−/−) mice die inutero at day 9.5. Enpp2^(+/−) mice show reduced LPA plasma levels (vanMeeteren et al., Mol Cell Biol (2006), 26, 5015-5022). LPA exerts itsextracellular biological effects through binding to G protein-coupledreceptors. So far, five different LPA receptors have been identified,LPAR1 (EDG2), LPAR2 (EDG4), LPAR3 (EDG7), LPAR4 (GPR23 and LPAR5(GPR92). All described LPA receptors belong to the class A(Rhodopsin-like class) of G protein-coupled receptors (GPCRs).

LPAR5 has been identified in mouse and human dorsal root ganglia andreduced perception of pain was seen in LPAR5^(−/−) mice (Oh et al., JBiol Chem (2008), 283, 21054-21064; Kinloch et al., Expert Opin TherTargets (2005), 9, 685-698). The coupling of LPARs to different Gprotein subunits in different cell types in concert with thedifferential expression of the various LPA receptors on the same cell isthe primary reason for the great variety of biological effects of LPA.The influence of LPA on the activation of human platelets has beendescribed in the early 1980s. 1-O-alkyl-sn-glycero-3-phosphate (analkyl-LPA) has been identified to be a more potent activator inplatelets compared to oleoyl-LPA (Simon et al., Biochem Biophys ResCommun (1982), 108, 1743-1750). Further studies pointed out that theso-called alkyl-LPA receptor is neither an EDG-type LPA receptor norGPR23 (Tokumura et al., Biochem J (2002), 365, 617-628; Noguchi et al.,J Biol Chem (2003), 278, 25600-25606; Khandoga et al., J Thromb Haemost(2007), 5 Supplement 2: P-M-246 (ISTH 2007)). When transiently expressedin the rat hepatoma cell line RH7777, LPAR5 can be activated morestrongly with alkyl-LPA than acyl-LPA (Williams et al., J Biol Chem(2009), 284, 14558-14571). These data were in line with the LPA-mediatedactivation observed for human blood platelets, in which the functionaleffect of alkyl-LPA, in terms of inducing platelet aggregation is morepronounced than the effect of acyl-LPA. In addition, the LPA-receptorsLPAR4 and LPAR5 are highly expressed by human platelets (Amisten et al.,Thromb Res (2008), 122, 47-57). In contrast to LPAR5, which is coupledto G_(q), LPAR4 couples to G_(s) and can therefore be excluded toparticipate in LPA-mediated activation of human platelets. Consequently,LPAR5 was discussed to be the central LPA-receptor responsible forLPA-mediated activation in human platelets (Khandoga et al., Platelets(2008), 19, 415-427). High expression of LPAR5 in human mast cell lineshas been demonstrated, for example by Lundequist (Lundequist, J AllergyClin Immunol (2008), 121, Suppl 1, Abstr 518), and further analyses.

Mast cells are part of the immune system and generated as precursorcells in the bone marrow, differentiating to mature mast cells in thehoming tissue. Mast cells participate in a variety of pathophysiologicalprocesses that range from antimicrobial defense to anaphylaxis andinflammatory arthritis and have thus been discussed to be related toallergic responses. When activated, mast cells degranulate and release aplethora of mediators (cytokines such as TNFa, MCP-1, Rantes) into theinterstitium. This indicates a direct contribution of mast cells toneuropathic pain by releasing algogenic mediators after degranulation.

Atherosclerosis is promoted by mast cells not only through the releaseof proinflammatory cytokines, mast cell deficiency attenuatesatherosclerosis in apolipoprotein E-deficient mice and infiltrates ofactivated mast cells can be observed at the site of coronaryatheromatous erosion or rupture in myocardial infarction (Sun et al.,Nat Med (2007), 13, 719-724; Smith et al., FASEB J (2008), 22, 1065.32;Kovanen et al., Circulation (1995), 92, 1084-1088). These data providesound evidence for the central role of mast cells in the development andprogression of atherosclerotic plaques. In the atherosclerotic plaquemast cells contribute to plaque growth and instability via release ofstored and newly synthesized mediators such as (a) inflammatorycytokines that lead to an increased invasion of monocytes and theirdifferentiation to macrophages, (b) angiogenic cytokines such as VEGFthat might induce angiogenesis in the plaque, with intraplaquehemorrhage leading to an increased risk of plaque rupture and (c)histamine, a vasoactive component known to enhance vascular permeabilitywith the potential risk of increased LDL influx available for foam cellformation. Although the absolute number of mast cells in atheroscleroticplaques is inferior to the number of other inflammatory cells in thesame region, LPA as a direct activating ligand of mast cells is presentat high concentrations in atherosclerotic plaques (Rother et al.,Circulation (2003), 108, 741-747).

Apart from the above discussed role of mast cells in atherosclerosis,the broad spectrum of mast cell functions explains why mast cells areinvolved in a variety of pathologies apart from allergic responsesrelated to pathologies with an inflammatory component. These diseasescomprise hyperalgesia, asthma, multiple sclerosis and angiogenesis toname only a few (Zuo et al., Pain (2003), 105, 467-479; Toews et al.,Biochim Biophys Acta (2002), 1582, 240-250; Norby, APMIS (2002), 110,355-371). Treatment of the human mast cell line LAD2 with a shorthairpin RNA targeting LPAR5 down-regulates LPAR5 expression andattenuates MIP-1β following LPA activation (Lundequist, J Allergy ClinImmunol (2008), 121, Suppl 1, Abstr 518).

Analyses of the LPA receptor profile in the murine microglia cell lineBV-2, confirmed a high expression of LPAR5 in microglia cells, which arelike mast cells a cell population of the inflammatory system. Thefinding that LPAR5 is highly expressed not only in mast cells but aswell in microglia cells underlines the central role of LPAR5 in thedevelopment and progression of inflammatory disorders, such ashyperalgesia, asthma, multiple sclerosis, angiogenesis and others.

Further experiments confirmed that in human platelets and in human mastcells and microglia cells LPAR5 is the key LPA-receptor responsible forLPA-mediated activation. In view of the relevance of LPAR5 for variousdisease states there is a need for compounds which efficiently inhibitLPAR5 and, for example, consequently inhibit mast cell activation, forexample in atherosclerotic plaques, or platelet activation inpathological settings, and allow novel therapeutic options for treatingdisorders. Thus, it is an object of the present invention to provideLPAR5 antagonists, which antagonize the effect of endogenous LPA on itsLPAR5 receptor and which have further advantageous properties, forinstance stability in plasma and liver and selectivity versus otherreceptors whose agonism or antagonism is not intended. This object isachieved in accordance with the invention by providing the pyrazolederivatives of the formula I, which exhibit excellent LPAR5 antagonisticactivity and are favorable agents with high bioavailability, and can beused for inhibiting platelet aggregation and treating thromboembolicdiseases, for example.

Further WO 2011/015501, WO 2009/109613, WO 2009/109616, WO 2009/109618and EP 0382276 describe specific 1-benzyl-indazole derivatives for thetreatment of diseases based on the expression of MCP-1, CX3CR1 and p40.GuoGang Tu et al, Journal of Enzyme Inhibition and Medicinal Chemistry,2011, 26(2), 222-230 describe some compounds derived from the1,5-diarylpyrazole scaffold with potency towards the inhibition of theCBI receptor. Self C. R. et al, Journal of Medicinal Chemistry, 1991,34, 772-777 disclose potential disease-modifying antirheumatic drugsincluding specific 1-phenyl-pyrazole derivatives.

A subject of the present invention are the compounds of the formula I,in any of their stereoisomeric forms or a mixture of stereoisomericforms in any ratio, and the pharmaceutically acceptable salt thereof,

wherein

-   R¹ is selected from the series consisting of hydrogen,    (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl,    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, Ar and Ar—(C₁-C₄)-alkyl-;-   R² and R³ are independently of each other selected from the series    consisting of hydrogen, halogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, Ar, Ar—(C₁-C₄)-alkyl-,    (C₁-C₄)-alkyl-O—, (C₃-C₇)-cycloalkyl-O—,    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-O—, Ar—O— and Ar—(C₁-C₄)-alkyl-O—,-   R⁴ and R⁵ are independently of each other selected from the series    consisting of hydrogen, fluorine and (C₁-C₆)-alkyl,-   or the groups R⁴ and R⁵ together with the carbon atom carrying them    form a (C₃-C₇)-cycloalkane ring which is unsubstituted or    substituted by one or more identical or different substituents    selected from the series consisting of fluorine and (C₁-C₄)-alkyl;-   R¹¹, R¹², R¹³ and R¹⁴ are independently of each other selected from    the series consisting of hydrogen and (C₁-C₄)-alkyl;-   Ar is selected from the series consisting of phenyl, naphthyl and an    aromatic, 5-membered or 6-membered, monocyclic heterocycle which    comprises one or two identical or different ring heteroatoms    selected from the series consisting of N, O and S, which are all    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of halogen,    (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, cyano and (C₁-C₄)-alkyl-O—;-   V is selected from the series consisting of R¹²—N(R¹³)—, and in this    case G and M are not present,-   or-   V is selected from the series consisting of —N(R¹⁴)—,    —N(R¹⁴)—(C₁-C₄)-alkyl-, —O— and —O—(C₁-C₄)-alkyl-, and in this case-   G is selected from the series consisting of a direct bond and    phenylene which is unsubstituted or substituted by one or more    identical or different substituents selected from the series    consisting of halogen, (C₁-C₄)-alkyl, cyano and (C₁-C₄)-alkyl-O—,    provided that G is not a direct bond if V is —N(R¹⁴)— or —O—, and-   M is selected from the series consisting of R¹¹—O—C(O)— and    R¹²—N(R¹³)—C(O)—;    wherein all alkyl groups are unsubstituted or substituted by one or    more fluorine substituents, and all cycloalkyl groups are    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of fluorine and    (C₁-C₄)-alkyl.

In one embodiment the present invention relates to compounds of theformula I, wherein

-   R¹ is selected from the series consisting of hydrogen,    (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, Ar and Ar—(C₁-C₄)-alkyl-;-   R² and R³ are independently of each other selected from the series    consisting of hydrogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, Ar, Ar—(C₁-C₄)-alkyl-,    (C₁-C₄)-alkyl-O—, (C₃-C₇)-cycloalkyl-O—,    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-O—, Ar—O— and Ar—(C₁-C₄)-alkyl-O—,-   R⁴ and R⁵ are independently of each other selected from the series    consisting of hydrogen and (C₁-C₆)-alkyl,-   or the groups R⁴ and R⁵ together with the carbon atom carrying them    form a (C₃-C₇)-cycloalkane ring which is unsubstituted or    substituted by one or more identical or different substituents    selected from the series consisting of fluorine and (C₁-C₄)-alkyl;-   R¹¹, R¹², R¹³ and R¹⁴ are independently of each other selected from    the series consisting of hydrogen and (C₁-C₄)-alkyl;-   Ar is selected from the series consisting of phenyl, naphthyl and an    aromatic, 5-membered or 6-membered, monocyclic heterocycle which    comprises one or two identical or different ring heteroatoms    selected from the series consisting of N, O and S, which are all    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of halogen,    (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, cyano and (C₁-C₄)-alkyl-O—;-   V is selected from the series consisting of —N(R¹⁴)—,    —N(R¹⁴)—(C₁-C₄)-alkyl- and —O—(C₁-C₄)-alkyl-, and-   G is selected from the series consisting of a direct bond and    phenylene which is unsubstituted or substituted by one or more    identical or different substituents selected from the series    consisting of halogen, (C₁-C₄)-alkyl, cyano and (C₁-C₄)-alkyl-O—,    provided that G is not a direct bond if V is —N(R¹⁴)—, and-   M is selected from the series consisting of R¹¹—O—C(O)— and    R¹²—N(R¹³)—C(O)—;    wherein all alkyl groups are unsubstituted or substituted by one or    more fluorine substituents, and all cycloalkyl groups are    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of fluorine and    (C₁-C₄)-alkyl;    and all stereoisomeric forms and mixtures of stereoisomeric forms in    any ratio, and the pharmaceutically acceptable salts thereof.

In another embodiment the present invention relates to compounds of theformula I, wherein

-   R¹ is selected from the series consisting of (C₁-C₆)-alkyl,    (C₃-C₇)-cycloalkyl, Ar and Ar—(C₁-C₄)-alkyl-;-   R² and R³ are independently of each other selected from the series    consisting of hydrogen, (C₁-C₄)-alkyl, Ar, Ar—(C₁-C₄)-alkyl-,    (C₁-C₄)-alkyl-O—, (C₃-C₇)-cycloalkyl-O—, Ar—O— and    Ar—(C₁-C₄)-alkyl-O—,-   R⁴ and R⁵ are independently of each other selected from the series    consisting of hydrogen and (C₁-C₆)-alkyl,-   or the groups R⁴ and R⁵ together with the carbon atom carrying them    form a (C₃-C₇)-cycloalkane ring which is unsubstituted or    substituted by one or more identical or different substituents    selected from the series consisting of fluorine and (C₁-C₄)-alkyl;-   R¹¹, R¹², R¹³ and R¹⁴ are independently of each other selected from    the series consisting of hydrogen and (C₁-C₄)-alkyl;-   Ar is selected from the series consisting of phenyl, naphthyl and an    aromatic, 5-membered or 6-membered, monocyclic heterocycle which    comprises one or two identical or different ring heteroatoms    selected from the series consisting of N, O and S, which are all    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of halogen,    (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl and (C₁-C₄)-alkyl-O—;-   V is selected from the series consisting of —N(R¹⁴)— and    —N(R¹⁴)—(C₁-C₄)-alkyl-, and-   G is selected from the series consisting of a direct bond and    phenylene which is unsubstituted or substituted by one or more    identical or different substituents selected from the series    consisting of halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, provided    that G is not a direct bond if V is —N(R¹⁴)—, and-   M is selected from the series consisting of R¹¹—O—C(O)— and    R¹²—N(R¹³)—C(O)—;    wherein all alkyl groups are unsubstituted or substituted by one or    more fluorine substituents, and all cycloalkyl groups are    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of fluorine and    (C₁-C₄)-alkyl;    and all stereoisomeric forms and mixtures of stereoisomeric form in    any ratio, and the pharmaceutically acceptable salts thereof.

In another embodiment the present invention relates to compounds of theformula I, wherein

-   R¹ is selected from the series consisting of (C₁-C₄)-alkyl, Ar and    Ar—(C₁-C₄)-alkyl-;-   R² and R³ are independently of each other selected from the series    consisting of hydrogen, (C₁-C₄)-alkyl, Ar, Ar—(C₁-C₄)-alkyl-, and    Ar—O—,-   R⁴ and R⁵ are independently of each other selected from the series    consisting of hydrogen and (C₁-C₆)-alkyl,-   or the groups R⁴ and R⁵ together with the carbon atom carrying them    form a (C₃-C₇)-cycloalkane ring which is unsubstituted or    substituted by one or more identical or different substituents    selected from the series consisting of fluorine and (C₁-C₄)-alkyl;-   R¹¹ and R¹⁴ are independently of each other selected from the series    consisting of hydrogen and (C₁-C₄)-alkyl;-   Ar is selected from the series consisting of phenyl, naphthyl and an    aromatic, 5-membered or 6-membered, monocyclic heterocycle which    comprises one or two identical or different ring heteroatoms    selected from the series consisting of N, O and S, which are all    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of halogen,    (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl and (C₁-C₄)-alkyl-O—;-   V is selected from the series consisting of —N(R¹⁴)— and    —N(R¹⁴)—(C₁-C₄)-alkyl-, and-   G is selected from the series consisting of a direct bond and    phenylene which is unsubstituted or substituted by one or more    identical or different substituents selected from the series    consisting of halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, provided    that G is not a direct bond if V is —N(R¹⁴), and-   M is R¹¹—O—C(O)—;    wherein all alkyl groups are unsubstituted or substituted by one or    more fluorine substituents, and all cycloalkyl groups are    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of fluorine and    (C₁-C₄)-alkyl;    and all stereoisomeric forms and mixtures of stereoisomeric forms in    any ratio, and the pharmaceutically acceptable salts thereof.

In another embodiment the present invention relates to compounds of theformula I, wherein

-   R¹ is selected from the series consisting of (C₁-C₄)-alkyl, Ar and    Ar—(C₁-C₄)-alkyl-;-   R² and R³ are independently of each other selected from the series    consisting of hydrogen, (C₁-C₄)-alkyl, Ar— and Ar—O—,-   R⁴ and R⁵ are independently of each other selected from the series    consisting of hydrogen and (C₁-C₆)-alkyl,-   or the groups R⁴ and R⁵ together with the carbon atom carrying them    form a (C₃-C₇)-cycloalkane ring which is unsubstituted or    substituted by one or more fluorine substituents;-   R¹¹ and R¹⁴ are independently of each other selected from the series    consisting of hydrogen and (C₁-C₄)-alkyl;-   Ar is selected from the series consisting of phenyl, naphthyl and an    aromatic, 5-membered or 6-membered, monocyclic heterocycle which    comprises one or two identical or different ring heteroatoms    selected from the series consisting of N, O and S, which are all    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of halogen,    (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl and (C₁-C₄)-alkyl-O—;-   V is selected from the series consisting of —N(R¹⁴)— and    —N(R¹⁴)—(C₁-C₄)-alkyl-, and-   G is selected from the series consisting of a direct bond and    phenylene which is unsubstituted or substituted by one or more    identical or different substituents selected from the series    consisting of halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, provided    that G is not a direct bond if V is —N(R¹⁴), and-   M is R¹¹—O—C(O)—;    wherein all alkyl groups are unsubstituted or substituted by one or    more fluorine substituents;    and all stereoisomeric forms and mixtures of stereoisomeric forms in    any ratio, and the pharmaceutically acceptable salts thereof.

In one embodiment compounds of the formula I are defined as above and R¹is selected from the series consisting of (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, Ar andAr—(C₁-C₄)-alkyl-, in another embodiment from the series consisting of(C₁-C₆)-alkyl, Ar and Ar—(C₁-C₄)-alkyl-, in another embodiment from theseries consisting of (C₁-C₄)-alkyl, Ar and Ar—(C₁-C₄)-alkyl-, in anotherembodiment from the series consisting of (C₁-C₆)-alkyl and Ar, inanother embodiment from the series consisting of (C₁-C₄)-alkyl and Ar,in another embodiment from the series consisting of Ar andAr—(C₁-C₄)-alkyl-, in another embodiment R¹ is Ar, wherein all Ar groupsare unsubstituted or substituted as specified. In one embodiment anAr—(C₁-C₄)-alkyl- group representing R¹ is an Ar—(C₁-C₂)-alkyl- group,in another embodiment an Ar—CH₂— group. In one embodiment a group Arrepresenting R¹ is a phenyl group which is unsubstituted or substitutedas specified. In one embodiment, a substituted Ar group or phenyl grouprepresenting R¹ is substituted by one, two or three, in anotherembodiment by one or two, in another embodiment by one, identical ordifferent substituents, wherein in one embodiment the substituents areselected from the series consisting of halogen, (C₁-C₄)-alkyl, cyano and(C₁-C₄)-alkyl-O—, in another embodiment from the series consisting ofhalogen, (C₁-C₄)-alkyl and cyano, in another embodiment from the seriesconsisting of halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, in anotherembodiment from the series consisting of halogen and (C₁-C₄)-alkyl, andin another embodiment they are identical or different halogensubstituents, for example chlorine.

In one embodiment compounds of the formula I are defined as above and R²and R³ are independently of each other selected from the seriesconsisting of hydrogen, halogen, (C₁-C₄)-alkyl, Ar, Ar—(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—, Ar—O— and Ar—(C₁-C₄)-alkyl-O—, in another embodimentfrom the series consisting of hydrogen, (C₁-C₄)-alkyl, Ar,Ar—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—, Ar—O— and Ar—(C₁-C₄)-alkyl-O—, inanother embodiment from the series consisting of hydrogen,(C₁-C₄)-alkyl, Ar, Ar—(C₁-C₄)-alkyl- and Ar—O—, in another embodimentfrom the series consisting of (C₁-C₄)-alkyl, Ar, Ar—(C₁-C₄)-alkyl- andAr—O—, in another embodiment from the series consisting of hydrogen,(C₁-C₄)-alkyl, Ar and Ar—O—, in another embodiment from the seriesconsisting of (C₁-C₄)-alkyl, Ar and Ar—O—, in another embodiment fromthe series consisting of hydrogen, (C₁-C₄)-alkyl and Ar, in anotherembodiment from the series consisting of (C₁-C₄)-alkyl and Ar, whereinall groups Ar occurring in R² and R³ are unsubstituted or substituted asspecified.

In one embodiment, one of the groups R² and R³ is group Ar or contains agroup Ar, and the other of the groups R² and R³ is selected from theseries consisting of hydrogen, (C₁-C₄)-alkyl and Ar, in anotherembodiment from the series consisting of (C₁-C₄)-alkyl and Ar, inanother embodiment from the series consisting of hydrogen and(C₁-C₄)-alkyl. In one embodiment, a group Ar occurring in R² or R³ isselected from the series consisting of phenyl, naphthyl and an aromatic,5-membered or 6-membered, monocyclic heterocycle which comprises onering heteroatom selected from the series consisting of N, O and S, inanother embodiment from the series consisting of phenyl and an aromatic,5-membered or 6-membered, monocyclic heterocycle which comprises onering heteroatom selected from the series consisting of N, O and S, inanother embodiment from the series consisting of phenyl, naphthyl andthienyl, in another embodiment from the series consisting of phenyl andthienyl, in another embodiment from the series consisting of phenyl andnaphthyl, and in another embodiment it is a phenyl group, which are allunsubstituted or substituted as specified. In one embodiment, the numberof substituents in a substituted group Ar occurring in R² or R³ is one,two or three, in another embodiment it is one or two, in anotherembodiment it is one. In one embodiment, the substituents on asubstituted group Ar occurring in R² or R³ are selected from the seriesconsisting of halogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, cyano and(C₁-C₄)-alkyl-O—, in another embodiment from the series consisting ofhalogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl and (C₁-C₄)-alkyl-O—, inanother embodiment from the series consisting of halogen and(C₁-C₄)-alkyl, wherein (C₁-C₄)-alkyl substituents are unsubstituted orsubstituted by one or more fluorine substituents. In one embodiment, a(C₁-C₄)-alkyl substituent present on a group Ar occurring in R² or R³ isa perfluoroalkyl group, for example a trifluoromethyl group CF₃. in oneembodiment, halogen substituents present on a group Ar occurring in R²or R³ are fluorine and/or chlorine substituents.

In one embodiment compounds of the formula I are defined as above and R⁴and R⁵ are independently of each other selected from the seriesconsisting of hydrogen, fluorine and (C₁-C₄)-alkyl, in anotherembodiment from the series consisting of hydrogen and (C₁-C₄)-alkyl, inanother embodiment from the series consisting of hydrogen and(C₁-C₃)-alkyl, in another embodiment from the series consisting ofhydrogen, methyl, ethyl, n-propyl and isopropyl, in another embodimentfrom the series consisting of hydrogen and methyl, and in anotherembodiment at least one of the groups R⁴ and R⁵ is different fromhydrogen, or the groups R⁴ and R⁵ together with the carbon atom carryingthem form a (C₃-C₇)-cycloalkane ring, in one embodiment a(C₄-C₆)-cycloalkane ring, in another embodiment a (C₅-C₆)-cycloalkanering, which cycloalkane rings are all unsubstituted or substituted asspecified.

In another embodiment compounds R⁴ and R⁵ are independently of eachother selected from the series consisting of hydrogen, fluorine and(C₁-C₄)-alkyl, in another embodiment from the series consisting ofhydrogen and (C₁-C₄)-alkyl, in another embodiment from the seriesconsisting of hydrogen and (C₁-C₃)-alkyl, in another embodiment from theseries consisting of hydrogen, methyl, ethyl, n-propyl and isopropyl, inanother embodiment from the series consisting of hydrogen and methyl.

In one embodiment one of the groups R⁴ and R⁵ is hydrogen and the otheris as defined, in another embodiment the groups R⁴ and R⁵ are bothhydrogen, in another embodiment at least one of the groups R⁴ and R⁵ isdifferent from hydrogen, in another embodiment the groups R⁴ and R⁵ areboth (C₁-C₄)-alkyl, in another embodiment the groups R⁴ and R⁵ are both(C₁-C₃)-alkyl, and in another embodiment the groups R⁴ and R⁵ are bothselected from the series consisting of methyl, ethyl, n-propyl andisopropyl. In one embodiment, the groups R⁴ and R⁵ are identical.

In another embodiment R⁴ and R⁵ form together with the carbon atomcarrying them a (C₃-C₇)-cycloalkane ring, in another embodiment a(C₄-C₆)-cycloalkane ring, in another embodiment a (C₅-C₆)-cycloalkanering, which cycloalkane rings are all unsubstituted or substituted asspecified. In general is the number of substituents in a substitutedcycloalkane ring formed by R⁴ and R⁵ together with the carbon atomcarrying them in one embodiment of the invention one, two, three orfour, in another embodiment one, two or three, in another embodiment oneor two, and in another embodiment a cycloalkane ring formed by R⁴ and R⁵together with the carbon atom carrying them is unsubstituted.

In one embodiment compounds of the formula I are defined as above andR¹¹, R¹², R¹³ and R¹⁴ are independently of each other selected from theseries consisting of hydrogen, methyl and ethyl, in another embodimentfrom the series consisting of hydrogen and methyl, and in anotherembodiment they are hydrogen.

In one embodiment compounds of the formula I are defined as above and Aris selected from the series consisting of phenyl and naphthyl, inanother embodiment from the series consisting of phenyl and an aromatic,5-membered or 6-membered, monocyclic heterocycle which comprises one ortwo identical or different ring heteroatoms selected from the seriesconsisting of N, O and S, in another embodiment one ring heteroatomselected from the series consisting of N, O and S, and in anotherembodiment Ar is phenyl, which are all unsubstituted or substituted byone or more identical or different substituents selected from the seriesconsisting of halogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, cyano and (C₁-C₄)-alkyl-O—, inanother embodiment from the series consisting of halogen, (C₁-C₄)-alkyl,(C₃-C₇)-cycloalkyl, cyano and (C₁-C₄)-alkyl-O—, in another embodimentfrom the series consisting of halogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyland (C₁-C₄)-alkyl-O—, in another embodiment from the series consistingof halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, in another embodimentfrom the series consisting of halogen, (C₁-C₄)-alkyl and(C₃-C₇)-cycloalkyl, in another embodiment from the series consisting ofhalogen and (C₁-C₄)-alkyl, wherein alkyl substituents can beunsubstituted or substituted by one or more fluorine substituents. Inone embodiment, a substituted group Ar carries one, two or threeidentical or different substituents, in another embodiment one or twoidentical or different substituents, in another embodiment onesubstituent, wherein all groups Ar are independent of each other.

If the divalent group V is the group —N(R¹⁴)—(C₁-C₄)-alkyl- or the group—O—(C₁-C₄)-alkyl-, the group G is bonded to the (C₁-C₄)-alkyl moietythereof. In one embodiment compounds of the formula I are defined asabove and V is selected from the series consisting of —N(R¹⁴)— and—N(R¹⁴)—(C₁-C₄)-alkyl-, and in this case G is selected from the seriesconsisting of a direct bond and phenylene, and in another embodiment isphenylene, wherein all phenylene groups are unsubstituted or substitutedby one or more identical or different substituents selected from theseries consisting of halogen, (C₁-C₄)-alkyl, cyano and (C₁-C₄)-alkyl-O—,provided that G is not a direct bond if V is —N(R¹⁴)—, and M isR¹¹—O—C(O)—, in another embodiment HO—C(O)—.

In another embodiment compounds of the formula I are defined as aboveand V is selected from the series consisting of R¹²—N(R¹³)— and in thiscase G and M are not present.

In another embodiment, V is selected from the series consisting of—N(R¹⁴)—, —N(R¹⁴)—(C₁-C₄)-alkyl-, —O— and —O—(C₁-C₄)-alkyl-, in anotherembodiment from the series consisting of —N(R¹⁴)— and—N(R¹⁴)—(C₁-C₄)-alkyl-, in another embodiment from the series consistingof —N(R¹⁴)— and —N(R¹⁴)—(C₁-C₃)-alkyl-, and in this case G is selectedfrom the series consisting of a direct bond and phenylene, and in oneembodiment is phenylene, wherein all phenylene groups are unsubstitutedor substituted as specified, provided that G is not a direct bond if Vis —N(R¹⁴)— or —O—, and M is R¹¹—O—C(O)— or R¹²—N(R¹³)—C(O)—, in anotherembodiment R¹¹—O—C(O)—, in another embodiment HO—C(O)—.

In one embodiment, G is a direct bond, in another embodiment G isphenylene which is unsubstituted or substituted as specified. In oneembodiment, a substituted phenylene group representing G carries one ortwo identical or different substituents, in another embodiment itcarries one substituent, which is selected from the series consisting ofhalogen and (C₁-C₄)-alkyl, and in another embodiment is halogen. In oneembodiment a phenylene group representing G is unsubstituted. In oneembodiment, a phenylene group representing G is selected from the seriesconsisting of 1,3-phenylene and 1,4-phenylene, in another embodiment itis 1,4-phenylene.

The group M-G-V—C(O)—C(R⁴)(R⁵)—O—CH₂— in the compounds of the formula Ican be bonded to any of the ring carbon atoms of the 1H-pyrazole ringdepicted in formula I, i.e. in position 3, in position 4 or in position5 of the 1H-pyrazole ring, as is symbolized by the free bond on the CH₂moiety of the said group, which bond is not directed to a specific ringcarbon atom. In one embodiment of the invention, the groupM-G-V—C(O)—C(R⁴)(R⁵)—O—CH₂— is bonded in position 3 of the pyrazole ringand the compound of the formula I thus is a compound of the formula Ia,in another embodiment the said group is bonded in position 4 of thepyrazole ring and the compound of the formula I thus is a compound ofthe formula Ib, and in another embodiment the said group is bonded inposition 5 of the pyrazole ring and the compound of the formula I thusis a compound of the formula Ic, in another embodiment the said group isbonded in position 3 or position 4, in another embodiment the said groupis bonded in position 3 or position 5, and in another embodiment thesaid group is bonded in position 4 or position 5.

Likewise can the groups R² and R³ in the compounds of the formula I aswell as in the compounds of the formulae Ia, Ib and Ic be bonded to anyring carbon atom of the pyrazole ring depicted in formula I which is notoccupied by the group M-G-V—C(O)—C(R⁴)(R⁵)—O—CH₂—, i.e. in positions 3and 4, in positions 3 and 5 or in positions 4 and 5 of the pyrazolering. The groups R¹ to R⁵, V, G and M in the compounds of the formulaIa, Ib and Ic are defined as in the compounds of the formula I.

In one embodiment of the invention, the compound of the formula I isselected from the series consisting of

-   4-({2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-2-methyl-propionylamino}-methyl)-benzoic    acid,-   4-({2-[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionylamino}-methyl)-benzoic    acid,-   4-({2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-acetylamino}-methyl)-benzoic    acid,-   4-({2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-butyrylamino}-methyl)-benzoic    acid,-   4-({2-[1-(2-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionylamino}-methyl)-benzoic    acid,-   4-({2-[1-(4-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionylamino}-methyl)-benzoic    acid,-   4-({2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-propionylamino}-methyl)-benzoic    acid,-   4-{2-[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-propionylamino}-benzoic    acid,-   4-{2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-3-methyl-butyrylamino}-benzoic    acid,-   4-{2-[1-(4-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-propionylamino}-benzoic    acid,-   4-[2-(3-Naphthalen-2-yl-1-phenyl-1H-pyrazol-4-ylmethoxy)-propionylamino]-benzoic    acid,-   4-{2-[1-(2-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-propionylamino}-benzoic    acid,-   4-[2-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethoxy)-propionylamino]-benzoic    acid,-   4-[2-(1,3-Diphenyl-1H-pyrazol-4-ylmethoxy)-propionylamino]-benzoic    acid,-   4-{2-[1-Benzyl-3-(3-methoxy-phenyl)-1H-pyrazol-4-ylmethoxy]-propionylamino}-benzoic    acid,-   4-{2-[5-(4-Fluoro-phenoxy)-1-methyl-3-phenyl-1H-pyrazol-4-ylmethoxy]-propionylamino}-benzoic    acid,-   4-{2-[3-(4-Cyclohexyl-phenyl)-1-phenyl-1H-pyrazol-4-ylmethoxy]-propionylamino}-benzoic    acid,-   4-[2-(1-Phenyl-3-thiophen-2-yl-1H-pyrazol-4-ylmethoxy)-propionylamino]-benzoic    acid, and-   4-[2-(1,5-Diphenyl-1H-pyrazol-3-ylmethoxy)-propionylamino]-benzoic    acid,    and all stereoisomeric forms and mixtures of stereoisomeric forms in    any ratio, and the pharmaceutically acceptable salts thereof.

If structural elements such as groups or substituents, for examplealkyl, cycloalkyl or Ar groups, can occur several times in the compoundsof the formula I, they are all independent of each other and can in eachcase have any of the indicated meanings, and they can in each case beidentical to or different from any other such element.

The term alkyl is to be understood as meaning a residue of a saturatedacyclic hydrocarbon which can be linear, i.e. straight-chain, orbranched. If not otherwise defined, alkyl has 1 to 6 carbon atoms or 1to 4 carbon atoms. Examples of (C₁-C₆)-alkyl and (C₁-C₄)-alkyl are alkylresidues containing 1, 2, 3, 4, 5 or 6 carbon atoms or 1, 2, 3 or 4carbon atoms, respectively, including methyl, ethyl, propyl, butyl,pentyl and hexyl, the n-isomers of these residues, isopropyl, isobutyl,1-methylbutyl, isopentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl,3-methylpentyl, isohexyl, sec-butyl, tert-butyl and tert-pentyl. Allthese statements also apply if an alkyl group is substituted or occursas a substituent on another residue, for example in an alkyl-O-residue(alkyloxy residue, alkoxy residue), an alkyl-O—C(O)— residue(alkyloxycarbonyl residue) or an aryl-alkyl- residue.

Alkyl groups can in general, independently of any other substituentswhich an alkyl groups carries, be unsubstituted or substituted by one ormore fluorine substituents, for example by one, two, three, four or fivefluorine substituents, or by one, two or three fluorine substituents.Such fluorine-substituted alkyl group can also be perfluoroalkyl groups,i.e. alkyl groups in which all hydrogen atoms are replaced by fluorineatoms. Examples of fluorine-substituted alkyl groups are —CF₃, —CHF₂,—CH₂F and —CF₂—CF₃, of which —CF₃ and —CF₂—CF₃ are examples ofperfluoroalkyl groups. In one embodiment, an alkyl group in anyoccurrence, independently of other occurrences, and independently of anyother substituents which the alkyl groups carries, is not substituted byfluorine, in another embodiment it is substituted by fluorine.

The term (C₃-C₇)-cycloalkyl is to be understood as meaning a residue ofa saturated cyclic hydrocarbon cycle containing from 3 to 7 ring carbonatoms in a monocyclic ring. Examples of (C₃-C₇)-cycloalkyl arecycloalkyl residues containing 3, 4, 5, 6 or 7 ring carbon atoms likecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Allcycloalkyl groups can be unsubstituted or substituted by one or more,for example one, two, three or four, identical or different substituentsselected from the series consisting of fluorine and (C₁-C₄)-alkyl. Inone embodiment, a cycloalkyl group is not substituted by fluorine and/oralkyl.

The term (C₃-C₇)-cycloalkane, which refers to the group which can beformed by R⁴ and R⁵ together with the carbon atom carrying them, is tobe understood as meaning a cyclopropane, cyclobutane, cyclopentane,cyclohexane or cycloheptane ring one ring carbon atom of which, which isthe carbon atom depicted in formula I which carries the groups R⁴ andR⁵, is bonded to the adjacent oxygen atom and C(O) group depicted informula I.

The term Ar is to be understood as meaning phenyl, naphthyl or a residueof an aromatic, 5-membered or 6-membered, monocyclic hydrocarbon ring,wherein in the said hydrocarbon ring one or two ring carbon atoms arereplaced by identical or different ring heteroatoms selected from theseries consisting of N, O and S, such as furanyl, pyridinyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazinyl, pyridazinyl,pyrimidinyl, pyrrolyl, pyrazolyl and thienyl residues, which can all beunsubstituted or substituted by one or more identical or differentsubstituents selected from the series consisting of halogen,(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-,cyano and (C₁-C₄)-alkyl-O—. Naphthyl can be 1-naphthyl and 2-naphthyl.

Halogen is fluorine, chlorine, bromine or iodine. In one embodiment,halogen is in any of its occurrences, independently of otheroccurrences, selected from the series consisting of fluorine, chlorinean bromine, in another embodiment from the series consisting of fluorineand chlorine.

Optically active carbon atoms present in the compounds of the formula Ican independently of each other have R configuration or S configuration.The compounds of the formula I can be present in the form of pureenantiomers or pure diastereomers or in the form of mixtures ofenantiomers and/or diastereomers in any ratio, for example in the formof racemates. The present invention relates to pure enantiomers andmixtures of enantiomers as well as to pure diastereomers and mixtures ofdiastereomers. The invention comprises mixtures of two or of more thantwo stereoisomers of the formula I, and it comprises all ratios of thestereoisomers in the mixtures. In case the compounds of the formula Ican be present as E isomers or Z isomers (or cis isomers or transisomers) the invention relates both to pure E isomers and pure Z isomersand to E/Z mixtures in all ratios. The invention also comprises alltautomeric forms of the compounds of the formula I.

Diastereomers, including E/Z isomers, can be separated into theindividual isomers, for example, by chromatography. Racemates can beseparated into the two enantiomers by customary methods, for example bychromatography on chiral phases or by resolution, for example bycrystallization of diastereomeric salts obtained with optically activeacids or bases. Stereochemically uniform compounds of the formula I canalso be obtained by employing stereochemically uniform startingmaterials or by using stereoselective reactions.

Pharmaceutically acceptable salts of the compounds of formula I areunderstood to be nontoxic salts that are physiologically acceptable andpharmaceutically utilizable salts. Such salts of compounds of theformula I containing acidic groups, for example a carboxyl group COOH,are for example alkali metal salts or alkaline earth metal salts such assodium salts, potassium salts, magnesium salts and calcium salts, andalso salts with pharmaceutically acceptable quaternary ammonium ionssuch as tetramethylammonium or tetraethylammonium, and acid additionsalts with ammonia and pharmaceutically acceptable organic amines, suchas methylamine, dimethylamine, trimethylamine, ethylamine,triethylamine, ethanolamine or tris-(2-hydroxyethyl)amine. Basic groupscontained in the compounds of the formula I form acid addition salts,for example with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid or phosphoric acid, or with organiccarboxylic acids and sulfonic acids such as formic acid, acetic acid,oxalic acid, citric acid, lactic acid, malic acid, succinic acid,malonic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid,methanesulfonic acid or p-toluenesulfonic acid. Compounds of the formulaI which simultaneously contain a basic group and an acidic group, canalso be present as zwitterions (betaines), which are likewise includedin the present invention.

Salts of compounds of the formula I can be obtained by customary methodsknown to those skilled in the art, for example by combining a compoundof the formula I with an inorganic or organic acid or base in a solventor dispersant, or from other salts by cation exchange or anion exchange.The present invention also includes all salts of the compounds of theformula I which, because of low physiologically tolerability, are notdirectly suitable for use in pharmaceuticals but are suitable, forexample, as intermediates for carrying out further chemicalmodifications of the compounds of the formula I or as starting materialsfor the preparation of pharmaceutically acceptable salts.

The invention also includes solvates, derivatives and modifications ofthe compounds of the formula I, for example prodrugs, protected formsand other pharmaceutically acceptable derivatives. The invention relatesin particular to prodrugs and protected forms of the compounds of theformula I, which can be converted into compounds of the formula I underphysiological conditions. Suitable prodrugs for the compounds of theformula I, i.e. chemically modified derivatives of the compounds of theformula I having properties which are improved in a desired manner, forexample with respect to solubility, bioavailability or duration ofaction, are known to those skilled in the art. More detailed informationrelating to prodrugs is found in standard literature like, for example,Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Fleisher et al.,Advanced Drug Delivery Reviews 19 (1996) 115-130; H. Bundgaard, Drugs ofthe Future 16 (1991) 443; Hydrolysis in Drug and Prodrug Metabolism, B.Testa, J. M. Mayer, Wiley-VCH, 2003.

Suitable prodrugs for the compounds of the formula I are especially acylprodrugs and carbamate prodrugs of acylatable nitrogen-containing groupssuch as amino groups and ester prodrugs and amide prodrugs of carboxylicacid groups which may be present in compounds of the formula I. In theacyl prodrugs and carbamate prodrugs a hydrogen atoms on a nitrogen atomin such groups is replaced with an acyl group or an ester group, forexample a (C₁-C₆)-alkyl-O—C(O)— group. Suitable acyl groups and estergroups for acyl prodrugs and carbamate prodrugs are, for example, thegroups R^(p1)—CO— and R^(p2)O—CO—, wherein R^(p1) can be hydrogen,(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-,Ar, (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl- or Ar—(C₁-C₄)-alkyl-,for example, and wherein R^(p2) has the meanings indicated for R^(p1)with the exception of hydrogen. The term (C₆-C₁₄)-aryl is understood asmeaning a residue of a monocyclic, bicyclic or tricyclic aromatichydrocarbon containing from 6 to 14 ring carbon atoms, for example 6, 7,8, 9, 10, 11, 12, 13 or 14 ring carbon atoms. Examples are phenyl,naphthyl, for example 1-naphthyl and 2-naphthyl, or biphenylyl.

Also with respect to all embodiments of the invention specified hereinit applies that the comprised compounds of the formula I are a subjectof the invention in all their stereoisomeric forms and mixtures ofstereoisomeric forms in any ratio, and in the form of theirpharmaceutically acceptable salts, as well as in the form of theirprodrugs.

The present invention also relates to processes for the preparation ofthe compounds of the formula I, by which the compounds are obtainableand which are another subject of the invention.

The compounds of the formula I can be prepared by utilizing proceduresand techniques, which per se are well known and appreciated by one ofordinary skill in the art. Starting materials or building blocks for usein the general synthetic procedures that can be applied in thepreparation of the compounds of formula I are readily available to oneof ordinary skill in the art. In many cases they are commerciallyavailable or have been described in the literature. Otherwise they canbe prepared from readily available precursor compounds analogously toprocedures described in the literature, or by procedures or analogouslyto procedures described herein.

In general, compounds of the formula I can be prepared, for example inthe course of a convergent synthesis, by linking two or more fragmentswhich can be derived retrosynthetically from the formula I. Morespecifically, suitably substituted starting pyrazole derivatives areemployed as building blocks in the preparation of the compounds offormula I. If not commercially available, such pyrazole derivatives canbe prepared according to the well-known standard procedures for theformation of the pyrazole ring system. By choosing suitable precursormolecules, these pyrazole syntheses allow the introduction of a varietyof substituents into the various positions of the pyrazole system, whichcan be chemically modified in order to finally arrive at the molecule ofthe formula I having the desired substituent pattern. As one of thecomprehensive reviews in which numerous details and literaturereferences on the chemistry of pyrazole and on synthetic procedures fortheir preparation can be found J. Eiguero in Comprehensive HeterocyclicChemistry II, Eds. A. Katritzky, Ch. Rees, E. Scriven, Elsevier 1996,Vol. 3; K. Kirschke in Houben-Weyl, Methoden der Organischen Chemie(Methods of Organic Chemistry), Georg Thieme Verlag, Stuttgart, Germany,1994, Vol. E8b Hetarene; T. Nagai et al. Org. Prep. Proced. Int. (1993),25, 403; M. Elnagdi et al. Heterocycles (1985) 23, 3121; K. Makino etal. J. Heterocycl. Chem. (1998) 35, 489; K. Makino et al. J. Heterocycl.Chem. (1999) 36, 321. If starting pyrazole derivatives are notcommercially available and have to be synthesized this can be done, forexample, according to the well-known pyrazole syntheses mentioned above.Depending on the substituents in the starting materials, in certainpyrazole syntheses mixtures of positional isomers may be obtained,which, however, can also be separated by modern separation techniqueslike, for example, preparative HPLC.

In the following, some procedures of interest for the synthesis of thecompounds of the invention are listed and referenced briefly. Theyillustrate some of the possible ways to access suitable pyrazolederivatives, and are standard procedures comprehensively discussed inthe literature and well known to one skilled in the art.

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-   19) F. Foti et al., Tetrahedron Lett. (1999) 40, 2605.

-   20) M. Martins et al., Synthesis (2003) 15, 2353.

-   21) J. Nef, Liebigs Ann. Chem. (1893) 276, 231.

-   22) Leighton, J. Am. Chem. Soc. (1898) 20, 677.

-   23) H. Ochi et al., Chem. Pham. Bull. (1983) 31, 1228.

Although not always shown explicitly, in certain cases positionalisomers will occur also during the synthesis by the mentioned reactions.Such mixtures of positional isomers can be separated by modernseparation techniques like, for example, preparative HPLC.

Further, in order to obtain the desired substituents at the pyrazolering system in the formula I, the functional groups introduced into thering system during the pyrazole synthesis can be chemically modified.Especially the substituents present on the pyrazole ring system can bemodified by a variety of reactions and thus the desired residues can beobtained. For example, a pyrazole carrying a hydrogen atom in a certainposition such as the 4-position can also be obtained by saponificationand subsequent decarboxylation of pyrazole carrying an ester group inthe relevant position. Halogen atoms can be introduced, for exampleaccording to procedures like the following described in the literature.For the fluorination of pyrazoles N-fluoro-2,4,6-trimethylpyridiniumtriflate can be used (T. Umemoto, S. Fukami, G. Tomizawa, K. Harasawa,K. Kawada, K. Tomita, J. Am. Chem. Soc. (1990) 112, 8563; see also K.Manko et al., J. Fluorine Chem. (1988) 39, 435; R. Storer et al.Nucleosides Nucleotides (1999) 18; 203). Other suitable fluorinatingreagents may also be employed where appropriate. The chlorination,bromination, or iodination of pyrazoles can be accomplished by thereaction with elemental halogens or by the use of N-halo-succinimideslike NCS, NBS or NIS and many other reagents well known to those skilledin the art. In addition suitable procedures are for example described byM. Rodriguez-Franco et al., Tetrahedron Lett. (2001) 42, 863; J. Pawlaset al., J. Org. Chem. (2000) 65, 9001; Y. Huang et al., Org Lett (2000)2, 2833; W. Holzer et al., J. Heterocycl. Chem. (1995) 32, 1351; N. Kudoet al., Chem. Pharm. Bull. (1999) 47, 857; G. Auzzi et al., Farmaco, EdSci. (1979) 34, 743; K. Morimoto et al., J. Heterocycl. Chem. (1997) 34,537; D. Jeon et al., Synth. Commun. (1998) 28, 2159. Depending on thereaction conditions, reagent, stoichiometry and substitution pattern thehalogen is introduced in the 3-position and/or 4-position and/or5-position. By selective halogen/metal exchange or metalation byselective hydrogen/metal exchange and subsequent reaction with a widerange of electrophiles various substituents can be introduced at theheterocyclic nucleus (M. R. Grimmett, Heterocycles (1994) 37, 2087; V.D. Gardner et al., J. Heterocycl. Chem. (1984), 21, 121; D. Butler etal., J. Org. Chem. (1971) 36, 2542). Among others, the correspondingpyrazolones can be useful precursors for the introduction of halogenatoms. For example, a 1H-pyrazol-3-ol can be converted to a5-chloro-1H-pyrazole by using phosphorous oxychloride, for example. The5-bromo-1H-pyrazole can be obtained from 1H-pyrazol-3-ol by similarstandard procedures using phosphorous oxybromide, phosphorous tribromideor phosphorous pentabromide.

Halogens, hydroxy groups (via the triflate or nonaflate) or primaryamines (via the diazonium salt), or after interconversion to thecorresponding stannanes and boronic acids, present in the pyrazolestructure can be converted into a variety of other functional groupslike for example —CN, —CF₃, —C₂F₅, ethers, acids, amides, amines, alkylor aryl groups mediated by means of transition metals, such as palladiumor nickel catalysts or copper salts and reagents for example referred tobelow (F. Diederich, P. Stang, Metal-catalyzed Cross-coupling Reactions,Wiley-VCH, 1998; M. Beller, C. Bolm, Transition Metals for OrganicSynthesis, Wiley-VCH, 1998; J. Tsuji, Palladium Reagents and Catalysts,Wiley, 1996; J. Hartwig, Angew. Chem. 1998, 110, 2154; B. Yang, S.Buchwald, J. Organomet. Chem. 1999, 576, 125; T. Sakamoto, K. Ohsawa, J.Chem. Soc. Perkin Trans I, 1999, 2323; D. Nichols, S. Frescas, D.Marona-Lewicka, X. Huang, B. Roth, G. Gudelsky, J. Nash, J. Med. Chem,1994, 37, 4347; P. Lam, C. Clark, S. Saubern, J. Adams, M. Winters, D.Chan, A. Combs, Tetrahedron Lett., 1998, 39, 2941; D. Chan, K. Monaco,R. Wang, M. Winters, Tetrahedron Lett. 1998, 39, 2933; V. Farina, V.Krishnamurthy, W. Scott, The Stille Reaction, Wiley, 1994; F. Qing etal. J. Chem. Soc. Perkin Trans. 11997, 3053; S. Buchwald et al. J. Am.Chem. Soc. 2001, 123, 7727; S. Kang et al. Synlett 2002, 3, 427; S.Buchwald et al. Organic Lett. 2002, 4, 581; T. Fuchikami et al.Tetrahedron Lett. 1991, 32, 91; Q. Chen et al. Tetrahedron Lett. 1991,32, 7689; M. R. Netherton, G. C. Fu, Topics in Organometallic Chemistry2005, 14, 85-108; A. F. Littke, G. F. Fu, Angew. Chem. Int. Ed. 2002,41, 4176-4211; A. R. Muci, S. L. Buchwald, Topics in Current Chemistry2002, 219, 131-209).

Ester groups present in the pyrazole nucleus can be hydrolyzed to thecorresponding carboxylic acids, which after activation can then bereacted with amines or alcohols under standard conditions. Furthermorethese ester or acid groups can be reduced to the corresponding alcoholsby many standard procedures. Ether groups present at the pyrazole, forexample benzyloxy groups or other easily cleavable ether groups, can becleaved to give hydroxy groups which then can be reacted with a varietyof agents, for example etherification agents or activating agentsallowing replacement of the hydroxy group by other groups.Sulfur-containing groups can be reacted analogously.

During the course of the synthesis in order to modify the groupsattached to the pyrazole ring system by application of parallelsynthesis methodology, besides a variety of reactions, palladium, nickelor copper catalysis can be extremely useful. Such reactions aredescribed for example in F. Diederich, P. Stang, Metal-catalyzedCross-coupling Reactions, Wiley-VCH, 1998; M. Beller, C. BoIm,Transition Metals for Organic Synthesis, Wiley-VCH, 1998; J. Tsuji,Palladium Reagents and Catalysts, Wiley, 1996; J. Hartwig, Angew. Chem.1998, 110, 2154; B. Yang, S. Buchwald, J. Organomet. Chem. 1999, 576,125; P. Lam, C. Clark, S. Saubern, J. Adams, M. Winters, D. Chan, A.Combs, Tetrahedron Lett. 1998, 39, 2941; D. Chan, K. Monaco, R. Wang, M.Winters, Tetrahedron Lett. 1998, 39, 2933; J. Wolfe, H. Tomori, J.Sadight, J. Yin, S. Buchwald, J. Org. Chem. 2000, 65, 1158; V. Farina,V. Krishnamurthy, W. Scott, The Stille Reaction, Wiley, 1994; S.Buchwald et al., J. Am. Chem. Soc. 2001, 123, 7727; S. Kang et al.,Synlett 2002, 3, 427; S. Buchwald et al., Org. Lett. 2002, 4, 581.

The previously-mentioned reactions for the conversion of functionalgroups are furthermore, in general, extensively described in textbooksof organic chemistry like M. Smith, J. March, March's Advanced OrganicChemistry, Wiley-VCH, 2001 and in treatises like Houben-Weyl, Methodender Organischen Chemie (Methods of Organic Chemistry), Georg ThiemeVerlag, Stuttgart, Germany; or Organic Reactions, John Wiley & Sons, NewYork; R. C. Larock, Comprehensive Organic Transformations, Wiley-VCH,2^(nd) ed., 1999; B. Trost, I. Fleming (eds.), Comprehensive OrganicSynthesis, Pergamon, 1991; A. Katritzky, C. Rees, E. Scriven,Comprehensive Heterocyclic Chemistry II, Elsevier Science, 1996, inwhich details on the reactions and primary source literature can befound. Due to the fact that in the present case the functional groupsare attached to a pyrazole ring it may in certain cases become necessaryto specifically adapt reaction conditions or to choose specific reagentsfrom a variety of reagents that can in principle be employed in aconversion reaction, or otherwise to take specific measures forachieving a desired conversion, for example to use protection grouptechniques. However, finding suitable reaction variants and reactionconditions in such cases does not cause any problems for one skilled inthe art. The structural elements attached to the pyrazole ring in thecompounds of the formula I can also be introduced into the startingpyrazole derivative using the methods outlined herein by consecutivereaction steps using parallel synthesis methodologies using procedureswhich per se are well known to one skilled in the art.

A subject of the present invention also is a process for preparing acompound of the formula I, which is outlined in the following scheme,

and which comprises

-   A) reducing a corresponding carboxylic acid or carboxylic acid ester    of a pyrazole derivative of the formula II to a pyrazole derivative    of the formula III carrying a hydroxymethylene group,-   B1) activating the hydroxymethylene group in the obtained pyrazole    derivative of the formula III by transformation into a leaving group    LG to give a pyrazole derivative of the formula IV, and subsequently    etherifying the latter compound with a hydroxy compound of the    formula V to obtain a pyrazole derivative of the formula I′, which    can already be the final compound of the formula I,-   or-   B2) reacting the obtained pyrazole derivative of the formula III    with an alkylating compound of the formula VI, wherein LG is a    leaving group, to obtain a pyrazole derivative of the formula I′,    which can already be the final compound of the formula I,-   C) optionally modifying the obtained compound of the formula I′ by    conversion and/or introduction any groups to give the final compound    of the formula I, and/or converting the compound into a    pharmaceutically acceptable salt thereof,-   D) isolating the final compound of the formula I or the    pharmaceutically acceptable salt thereof;    wherein    in the compounds of the formulae II, III, IV, V, VI and I′ the    residues R^(1′), R^(2′), R^(3′), R^(4′), R^(5′), V′, G′ and M′ are    defined as in the compound of the formula I, and additionally    functional groups can be present in protected form or in the form of    precursor groups which are subsequently converted into the final    groups present in the compound of the formula I;-   LG is a leaving group such as halogen like chlorine or bromine, a    sulfonyloxy group like methanesulfonyloxy or    4-methylbenzenesulfonyloxy, an azide group, or a diazonium group,    for example; and-   R¹⁰¹ is (C₁-C₆)-alkyl-O— or HO—, for example.

Compounds of the formula III can be obtained, for example, by reductionof a corresponding carboxylic acid or carboxylic ester of the formula IIusing well-known procedures and reagents like for example BH₃, NaBH₄ orLiAlH₄.

If structural features present in the pyrazole derivatives of theformula I, which are contained in the compounds of the formula V or theformula VI, have not already been introduced during a preceding step,for example during a synthesis of the pyrazole nucleus, the respectivegroups can, for example, be introduced into the pyrazole system bystandard alkylation procedures well-known to one skilled in the art. Thestarting pyrazole derivative III that is to be employed in such areaction carries a hydroxymethylen group. Alkylation of theaforementioned group can, for example, be performed under standardconditions, preferably in the presence of a base like K₂CO₃, Cs₂CO₃, NaHor KOtBu, using an alkylating compound of the formula VI wherein LG is aleaving group, such as for example halogen like chlorine, bromine oriodine, or a sulfonyloxy group like tosyloxy, mesyloxy ortrifluormethylsulfonyloxy. Alternatively, the hydroxymethylene group ofa pyrazole derivative of the formula III can be activated bytransformation into a leaving group LG by conversion into ahalomethylene group or sulfonyloxymethylene group liketosyloxymethylene, mesyloxymethylene ortrifluormethylsulfonyloxymethylene to give a pyrazole derivatives of theformula IV. These pyrazole derivatives of the formula IV can then beetherified, for example, under standard conditions, preferably in thepresence of a base like K₂CO₃, Cs₂CO₃, NaH or KOtBu, using a hydroxyderivative of the formula V. These standard procedures are for exampledescribed in treatises like M. Smith, J. March, March's Advanced OrganicChemistry, Wiley-VCH, 2001; Houben-Weyl, Methoden der Organischen Chemie(Methods of Organic Chemistry), Georg Thieme Verlag, Stuttgart, Germany;Organic Reactions, John Wiley & Sons, New York; R. C. Larock,Comprehensive Organic Transformations, Wiley-VCH, 2^(nd) ed., 1999; B.Trost, I. Fleming (eds.), Comprehensive Organic Synthesis, Pergamon,1991.

The group LG may, for example, also be a hydroxy group which, in orderto achieve the alkylation reaction, can be activated under thewell-known conditions of the Mitsunobu procedure (0. Mitsunobu,Synthesis 1981, 1) or by further modified procedures (A. Tunoori, D.Dutta, G. Gunda, Tetrahedron Lett. 39 (1998) 8751; J. Pelletier, S.Kincaid, Tetrahedron Lett. 41 (2000) 797; D. L. Hughes, R. A. Reamer, J.J. Bergan, E. J. J. Grabowski, J. Am. Chem. Soc. 110 (1998) 6487; D. J.Camp, I. D. Jenkins, J. Org. Chem. 54 (1989) 3045; D. Crich, H. Dyker,R. J. Harris, J. Org. Chem. 54 (1989) 257).

The compounds of the formulae II, III, IV, V, VI and I′ obtainedaccording to the reactions described herein can already contain thedesired final groups, i.e. R^(1′), R^(2′), R^(3′), R^(4′), R^(5′), V′,G′ and M′ can be the groups R¹, R², R³, R⁴, R⁵, V, G and M as defined informula I, or optionally in the compounds of the formulae II, Ill, IV,V, VI and I′ the residues R^(1′), R^(2′), R^(3′), R^(4′), R^(5′), V′, G′and M′ are subsequently converted into the residues R¹, R², R³, R⁴, R⁵,V, G and M to give the desired compound of the formula I. Thus, theresidues R¹, R^(2′), R^(3′), R^(4′), R^(5′), V′, G′ and M′ contained inthe compounds of the formulae II, III, IV, V, VI and I′ can have thedenotations of the residues in the compounds of the formula I, or inaddition they can also be present in the form of groups that cansubsequently be transformed into the final groups of the formula I and,for example, functional groups can be present in the form of precursorgroups or of derivatives or in protected form. In the course f thepreparation of the compounds of the formula I it can generally beadvantageous or necessary to introduce functional groups which reduce orprevent undesired reactions or side reactions in the respectivesynthesis steps, in the form of precursor groups which are laterconverted into the desired functional groups, or to temporarily blockfunctional groups by a protective group strategy suited to the synthesisproblem. Such strategies are well known to those skilled in the art(see, for example, Greene and Wuts, Protective Groups in OrganicSynthesis, Wiley, 1991; or P. Kocienski, Protecting Groups, Thieme,1994). Examples of precursor groups are cyano groups and nitro groups.The cyano group can, in a later step, be transformed into carboxylicacid derivatives or by reduction into aminomethyl groups. Nitro groupsmay be transformed by reduction like catalytic hydrogenation into aminogroups. Protective groups can also have the meaning of a solid phase,and cleavage from the solid phase stands for the removal of theprotective group. The use of such techniques is known to those skilledin the art (Burgess K (Ed.) Solid Phase Organic Synthesis, New York,Wiley, 2000). For example, a phenolic hydroxy group can be attached to atrityl-polystyrene resin, which serves as a protecting group, and themolecule is cleaved from this resin by treatment with trifluoroaceticacid (TFA) or other acids at a later stage of the synthesis.

The residue —V′-G′-M′ in the compounds of the formulae V, VI and I′,which can be identical or different, can be, for example, hydroxy or(C₁-C₄)-alkoxy, i.e., the groups —C(O)—V′-G′-M′ present in the compoundsof the formulae V, VI and I′ can be, for example, the free carboxylicacids or esters thereof like alkyl esters. The groups can also be anyother activated derivative of a carboxylic acid which allows amide orester formation with a compound of the formula H—V′-G′-M′. The activatedderivative can be, for example, an acid chloride, an activated esterlike a substituted phenyl ester or thioester, an azolide like animidazolide, an azide or a mixed anhydride, for example a mixedanhydride with a carbonic acid ester or with a sulfonic acid. Thesederivatives can all be prepared from the carboxylic acid by standardprocedures and can be reacted with an amine or alcohol of the formulaH—V′-G′-M′ under standard conditions. A carboxylic acid group —COOHrepresenting —C(O)—V′-G′-M′ in a compound of the formulae V and VI canbe obtained, for example by standard hydrolysis procedures, from anester group introduced into the pyrazole system during a pyrazolesynthesis.

Compounds of the formula I in which a group —C(O)—V′-G′-M′ is an amidegroup can be prepared from amines and compounds is a carboxylic acidgroup or an ester or thioester thereof by common amidation reactions.Especially for the preparation of amides the compounds containing acarboxylic acid group can be condensed under standard conditions withcompounds of the formula H—V′-G′-M′ which are amines by means of commoncoupling reagents used in peptide synthesis. Such coupling reagents are,for example, carbodiimides like dicyclohexylcarbodiimide (DCC) ordiisopropylcarbodiimide, carbonyldiazoles like carbonyldiimidazole (CU)and similar reagents, propylphosphonic anhydride,O-((cyano-(ethoxycarbonyl)-methylene)amino)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TOTU), diethylphosphoryl cyanide (DEPC),bis-(2-oxo-3-oxazolidinyl)-phosphoryl chloride (BOP-Cl),O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU), bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (Pybrop) and many others.

The activation of the carboxylic acid function may also favorably becarried out, for example, by conversion of the carboxylic acid groupinto the pentafluorophenyl ester using dicyclohexylcarbodiimide andpentafluorophenol or by using reagents like pentafluorophenyltrifluoroacetate, tert-butyl pentafluorophenyl carbonate,bis(pentafluorophenyl)carbonate, -pentafluorophenyl4-methylbenzenesulfonate, pentafluorophenyl-tetramethyluroniumhexafluorophosphate, octafluoroacetophenone. The activation of thecarboxylic function by conversion to other phenyl esters like forexample 4-nitro-phenyl esters or 2-nitro-phenyl esters can be alsoeffective. The activation and the subsequent reaction with a group ofthe formula H—V′-G′-M′ are usually carried out in the presence of aninert solvent or diluent, for example dichloromethane, chloroform,tetrahydrofuran (THF), diethyl ether, n-heptane, n-hexane, n-pentane,cyclohexane, diisopropyl ether, methyl tert-butyl ether, acetonitrile,N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA),N-methylpyrrolidin-2-one (NMP), dimethyl sulfoxide, dioxane, toluene,benzene, ethyl acetate or a mixture of these solvents, if appropriatewith addition of a base such as, for example, potassium tert-butoxide ortributylamine or triethylamine or diisopropylethylamine orN-ethylmorpholine.

The residues R^(1′), R^(2′), R^(3′), R^(4′), R^(5′) present in apyrazole of the formulae II, III, IV, V, VI and I′, or a residue inwhich functional groups within the residue are present in protected formor in the form of a precursor group, can for example be introduced intothe pyrazole system by conventional literature procedures for thealkylation, arylation, amination, etherification or thioetherificationof pyrazoles well-known to those skilled in the art. The appropriatelysubstituted pyrazole useful for these reactions carries a leaving grouplike for example halogen, triflate, nonaflate, tosylate, azide, or adiazonium salt. Preferably the reaction is carried out in the presenceof a base like K₂CO₃, Cs₂CO₃, NaH or KOtBu. The desired transformationcan also be accomplished with halogens, hydroxy groups (via the triflateor nonaflate) or primary amines (via the diazonium salt) or afterinterconversion to the corresponding stannane, or boronic acid—presentin the pyrazole structure—can be converted into a variety of otherfunctional groups like for example —CN, —CF₃, —C₂F₅, ethers, acids,amides, amines, alkyl or aryl groups mediated by means of transitionmetals, such as palladium or nickel catalysts or copper salts andreagents for example referred to below (F. Diederich, P. Stang,Metal-catalyzed Cross-coupling Reactions, Wiley-VCH, 1998; M. Beller, C.BoIm, Transition Metals for Organic Synthesis, Wiley-VCH, 1998; J.Tsuji, Palladium Reagents and Catalysts, Wiley, 1996; J. Hartwig, Angew.Chem. 1998, 110, 2154; B. Yang, S. Buchwald, J. Organomet. Chem. 1999,576, 125; T. Sakamoto, K. Ohsawa, J. Chem. Soc. Perkin Trans I, 1999,2323; D. Nichols, S. Frescas, D. Marona-Lewicka, X. Huang, B. Roth, G.Gudelsky, J. Nash, J. Med. Chem., 1994, 37, 4347; P. Lam, C. Clark, S.Saubern, J. Adams, M. Winters, D. Chan, A. Combs, Tetrahedron Lett.,1998, 39, 2941; D. Chan, K. Monaco, R. Wang, M. Winters, TetrahedronLett. 1998, 39, 2933; V. Farina, V. Krishnamurthy, W. Scott, The StilleReaction, Wiley, 1994; F. Qing et al. J. Chem. Soc. Perkin Trans. 11997,3053; S. Buchwald et al. J. Am. Chem. Soc. 2001, 123, 7727; S. Kang etal. Synlett 2002, 3, 427; S. Buchwald et al. Organic Lett. 2002, 4, 581;T. Fuchikami et al. Tetrahedron Lett. 1991, 32, 91; Q. Chen et al.Tetrahedron Lett. 1991, 32, 7689; M. R. Netherton, G. C. Fu, Topics inOrganometallic Chemistry 2005, 14, 85-108; A. F. Littke, G. F. Fu,Angew. Chem. Int. Ed. 2002, 41, 4176-4211; A. R. Muci, S. L. Buchwald,Topics in Current Chemistry 2002, 219, 131-209.

The compounds of the formula I are effective LPAR5 antagonists whichantagonize the effect of endogenous LPA on its LPAR5 receptor. Inparticular are the compounds of the formula I effective platelet, mastcell and microglial cell LPA receptor LPAR5 antagonists. The compoundsof the invention antagonize the platelet aggregating effect of theactivation of the platelet LPA receptor LPAR5, the LPA-mediatedactivation of human mast cells and the LPA-mediated activation ofmicroglia cells. In addition, the compounds of the formula I of theinvention also have further advantageous properties, for instancestability in plasma and liver and selectivity versus other receptorswhose agonism or antagonism is not intended. This good selectivity, forexample, makes it possible to reduce potential side effects existingwith regard to molecules having inadequate selectivity.

A subject of the present invention also are the compounds of the formulaI and/or the pharmaceutically acceptable salts thereof and/or prodrugsthereof for use as a medicament or as a pharmaceutical, andpharmaceutical compositions which comprise an effective amount of atleast one compound of the formula I and/or a pharmaceutical acceptablesalt thereof and/or a prodrug thereof and a pharmaceutically acceptablecarrier, i.e. one or more pharmaceutically acceptable carrier substancesor excipients and/or auxiliary substances or additives, and can beemployed in human, veterinary or phytoprotective use.

The activity of the compounds of the formula I can be determined, forexample, in the assays described below or in other in vitro or ex vivoassays known to those skilled in the art. The ability of the compoundsto inhibit LPA-induced aggregation of platelets may be measured bymethods similar to those described in the literature (for example, Holuband Waston in Platelets: A Practical Approach, pp 236-239, OxfordUniversity Press 1996) and by the methods described below. The resultsof these assays clearly demonstrate that the compounds of the inventionare functional antagonists of the platelet LPA receptor LPAR5 and aretherefore useful for inhibiting platelet aggregation and thrombusformation. The ability of the compounds to inhibit LPA-inducedactivation of mast cells or microglial cells may also be measured byusing the FLIPR system.

As LPA receptor LPAR5 antagonists, the compounds of the formula I and/ortheir pharmaceutically acceptable salts and/or their prodrugs aregenerally suitable for the treatment, including therapy and prophylaxis,of conditions in which the activity of LPAR5 receptor plays a role orhas an undesired extent, or which can favorably be influenced byinhibiting LPAR5 receptors or decreasing the activity, or for theprevention, alleviation or cure of which an inhibition of LPA receptorLPAR5 or a decrease in the activity is desired by the physician.

Thus, a subject of the invention also are the compounds of the formula Iand/or the pharmaceutically acceptable salts thereof and/or the prodrugsthereof for the use in the treatment, including therapy and prophylaxis,of a disease or disease state responsive to the inhibition of the LPAreceptor LPAR5 and/or the reduction or inhibition of plateletaggregation or thrombus formation and/or the reduction or inhibition ofactivation of mast cells and/or the reduction or inhibition ofactivation of microglial cells.

A subject of the invention also is the use of a compound of the formulaI and/or the pharmaceutically acceptable salts thereof and/or theprodrugs thereof for the manufacture of a medicament for the treatment,including therapy and prophylaxis, of a disease or disease stateresponsive to the inhibition of the LPA receptor LPAR5 and/or thereduction or inhibition of platelet aggregation or thrombus formationand/or the reduction or inhibition of activation of mast cells and/orthe reduction or inhibition of activation of microglial cells.

As inhibition of the LPA receptor LPAR5 influences platelet activationand platelet aggregation, the compounds of the formula I and/or theirpharmaceutically acceptable salts and/or their prodrugs are generallysuitable for reducing blood thrombus formation, or for the treatment,including therapy and prophylaxis, of conditions and diseases in whichthe activity of the platelet aggregation plays a role or has anundesired extent, or which can favorably be influenced by reducingthrombus formation, or for the prevention, alleviation or cure of whicha decreased activity of the platelet aggregation system is desired bythe physician. A specific subject of the present invention thus is thereduction or inhibition of unwanted thrombus formation, in particular inan individual, by administering an effective amount of a compound of theformula I and/or a pharmaceutically acceptable salt and/or a prodrugthereof, as well as pharmaceutical compositions therefore.

As inhibition of the LPA receptor LPAR5 influences mast cell activationthe compounds of the formula I and/or their pharmaceutically acceptablesalts and/or their prodrugs are generally suitable for reducing mastcell activation, or for the treatment, including therapy andprophylaxis, of conditions and diseases in which the activity of mastcells plays a role or has an undesired extent, or which can favorably beinfluenced by reducing mast cell activation, or for the prevention,alleviation or cure of which a decreased activity of the mast cellsystem is desired by the physician. A specific subject of the presentinvention thus is the reduction or inhibition of unwanted activation ofmast cells, in particular in an individual, by administering aneffective amount of a compound of the formula I and/or apharmaceutically acceptable salt and/or a prodrug thereof, as well aspharmaceutical compositions therefore.

As inhibition of the LPA receptor LPAR5 influences microglial cellactivation the compounds of the formula I and/or their pharmaceuticallyacceptable salts and/or their prodrugs are generally suitable forreducing microglial cell activation, or for the treatment, includingtherapy and prophylaxis, of conditions in which the activity ofmicroglial cells plays a role or has an undesired extent, or which canfavorably be influenced by reducing microglial cell activation, or forthe prevention, alleviation or cure of which a decreased activity of themicroglial cell system is desired by the physician. A specific subjectof the present invention thus are the reduction or inhibition ofunwanted activation of microglial cell, in particular in an individual,by administering an effective amount of a compound of the formula Iand/or a pharmaceutically acceptable salt and/or a prodrug thereof, aswell as pharmaceutical compositions therefore.

The present invention also relates to the compounds of the formula Iand/or their pharmaceutically acceptable salts and/or their prodrugs forthe use in the treatment, including therapy and prophylaxis, ofthromboembolic diseases, such as deep vein thrombosis, venous andarterial thromboembolism, thrombophlebitis, coronary and cerebralarterial thrombosis, cerebral embolism, renal embolism, pulmonaryembolism, disseminated intravascular coagulation, cardiovasculardisorders, such as transient ischemic attacks, strokes, acute myocardialinfarction, unstable angina, chronic stable angina, peripheral vasculardisease, preeclampsia/eclampsia, and thrombotic cytopenic purpura anddevelopment and progression of inflammatory disorders, such ashyperalgesia, asthma, multiple sclerosis, inflammatory pain,angiogenesis, atherothrombosis or allergic responses, or restenoses.

The present invention also relates to the use of the compounds of theformula I and/or their pharmaceutically acceptable salts and/or theirprodrugs for the manufacture of pharmaceutical compositions ormedicaments for inhibition of the LPA receptor LPAR5 or for influencingplatelet activation, platelet aggregation and platelet degranulation andpromote platelet disaggregation, inflammatory response and/or for thetreatment, including therapy and prophylaxis of the diseases mentionedabove or below, for example for the production of medicaments for thetreatment, including therapy and prophylaxis, of cardiovasculardisorders, thromboembolic diseases or restenosis, for the treatment ofdeep vein thrombosis, venous and arterial thromboembolism,thrombophlebitis, coronary and cerebral arterial thrombosis, cerebralembolism, renal embolism, pulmonary embolism, disseminated intravascularcoagulation, transient ischemic attacks, strokes, acute myocardialinfarction, unstable angina, chronic stable angina, peripheral vasculardisease, preeclampsia/eclampsia, and thrombotic cytopenic purpura anddevelopment and progression of inflammatory disorders, such ashyperalgesia, asthma, multiple sclerosis, angiogenesis, allergicresponses and others.

The invention also relates to the compounds of the formula I and/ortheir pharmaceutically acceptable salts and/or their prodrugs for theuse in the treatment, including therapy and prophylaxis, of the diseasesmentioned above or below, for example for use in the treatment ofcardiovascular disorders, thromboembolic diseases, atherothrombosis orrestenoses, and to methods of treatment aiming at such purposesincluding methods for said therapies and prophylaxis.

Due to the central role of the platelet LPA receptor LPAR5 inLPA-mediated activation of platelets, the invention also relates tocompounds of the formula I and/or the pharmaceutically acceptable saltsthereof for the use in the treatment, including therapy and prophylaxis,of disease states such as abnormal thrombus formation, acute myocardialinfarction, unstable angina, thromboembolism, acute vessel closureassociated with thrombolytic therapy or percutaneous transluminalcoronary angioplasty (PTCA), transient ischemic attacks, stroke,intermittent claudication or bypass grafting of the coronary orperipheral arteries, vessel luminal narrowing, restenosis post coronaryor venous angioplasty, maintenance of vascular access patency inlong-term hemodialysis patients, pathologic thrombus formation occurringin the veins of the lower extremities following abdominal, knee or hipsurgery, a risk of pulmonary thromboembolism, or disseminated systemicintravascular coagulatopathy occurring in vascular systems during septicshock, certain viral infections or cancer. The invention also relates tothe use of a compound of the formula I and/or the pharmaceuticallyacceptable salts thereof for the manufacture of a medicament for thetreatment, including therapy and prophylaxis of said disease states.

Due to the central role of the LPA receptor LPAR5 in LPA-mediatedactivation of mast cells and/or microglia cells, the invention alsorelates to compounds of the formula I and/or the pharmaceuticallyacceptable salts thereof for the use in the treatment, including therapyand prophylaxis, of disease states such as inflammatory pain, asthma,angiogenesis, demyelating diseases of (a) the central nervous systemsuch as, multiple sclerosis, transverse myelitis, optic neuritis,Devic's disease and (b) the peripheral nervous system such asGuillain-Barre syndrome or chronic inflammatory demyelinatingpolyneuropathy, as well as to the use of a compound of the formula Iand/or the pharmaceutically acceptable salts thereof for the manufactureof a medicament for the treatment, including therapy and prophylaxis ofsaid disease states.

The compounds of the formula I and their pharmaceutically acceptablesalts and their prodrugs can be administered to animals, preferably tomammals, and in particular to humans as pharmaceuticals for therapy orprophylaxis. They can be administered alone, or in mixtures with oneanother or in the form of pharmaceutical compositions, which permitenteral or parenteral administration.

The pharmaceutical compositions according to the invention can beadministered orally, for example in the form of pills, tablets,lacquered tablets, coated tablets, granules, hard and soft gelatinecapsules, solutions, syrups, emulsions, suspensions or aerosol mixtures.Administration can also be carried out rectally, for example in the formof suppositories, or parenterally, for example intravenously,intramuscularly or subcutaneously, in the form of injection solutions orinfusion solutions, microcapsules, implants or rods, or percutaneouslyor topically, for example in the form of ointments, solutions ortinctures, or in other ways, for example in the form of aerosols ornasal sprays.

The pharmaceutical compositions according to the invention are preparedin a manner known per se and familiar to one skilled in the art,pharmaceutically acceptable inert inorganic and/or organic carriersubstances and/or auxiliary substances being used in addition to one ormore compounds of the formula I and/or their pharmaceutically acceptablesalts and/or their prodrugs. For the production of pills, tablets,coated tablets and hard gelatine capsules it is possible to use, forexample, lactose, cornstarch or derivatives thereof, talc, stearic acidor its salts, etc. Carrier substances for soft gelatine capsules andsuppositories are, for example, fats, waxes, semisolid and liquidpolyols, natural or hardened oils, etc. Suitable carrier substances forthe production of solutions, for example injection solutions, or ofemulsions or syrups are, for example, water, saline, alcohols, glycerol,polyols, sucrose, invert sugar, glucose, vegetable oils, etc. Suitablecarrier substances for microcapsules, implants or rods are, for example,copolymers of glycolic acid and lactic acid. The pharmaceuticalcompositions normally contain about 0.5% to about 90% by weight of thecompounds of the formula I and/or their pharmaceutically acceptablesalts and/or their prodrugs. The amount of the active ingredient of theformula I and/or its pharmaceutically acceptable salts and/or itsprodrugs in the pharmaceutical compositions normally is from about 0.5mg to about 1000 mg, preferably from about 1 mg to about 500 mg.

In addition to the active ingredients of the formula I and/or theirpharmaceutically acceptable salts and/or prodrugs and to carriersubstances or excipients, the pharmaceutical compositions can containauxiliary substances or additives such as, for example, fillers,disintegrants, binders, lubricants, wetting agents, stabilizers,emulsifiers, preservatives, sweeteners, colorants, flavorings,aromatizers, thickeners, diluents, buffer substances, solvents,solubilizers, agents for achieving a depot effect, salts for alteringthe osmotic pressure, coating agents or antioxidants. They can alsocontain two or more compounds of the formula I, and/or theirpharmaceutically acceptable salts and/or their prodrugs. In case apharmaceutical composition contains two or more compounds of the formulaI, the selection of the individual compounds can aim at a specificoverall pharmacological profile of the pharmaceutical composition. Forexample, a highly potent compound with a shorter duration of action maybe combined with a long-acting compound of lower potency. Theflexibility permitted with respect to the choice of substituents in thecompounds of the formula I allows a great deal of control over thebiological and physico-chemical properties of the compounds and thusallows the selection of such desired compounds. Furthermore, in additionto at least one compound of the formula I and/or a pharmaceuticallyacceptable salt and/or its prodrug, the pharmaceutical compositions canalso contain one or more other pharmaceutically, therapeutically and/orprophylactically active ingredients.

When using the compounds of the formula I the dose can vary within widelimits and, as is customary and is known to the physician, is to besuited to the individual conditions in each individual case. It depends,for example, on the specific compound employed, on the nature andseverity of the disease to be treated, on the mode and the schedule ofadministration, or on whether an acute or chronic condition is treatedor whether prophylaxis is carried out. An appropriate dosage can beestablished using clinical approaches well known in the medical art. Ingeneral, the daily dose for achieving the desired results in an adultweighing about 75 kg is from 0.01 mg/kg to 100 mg/kg, preferably from0.1 mg/kg to 50 mg/kg, in particular from 0.1 mg/kg to 10 mg/kg, (ineach case in mg per kg of body weight). The daily dose can be divided,in particular in the case of the administration of relatively largeamounts, into several, for example 2, 3 or 4, part administrations. Asusual, depending on individual behavior it may be necessary to deviateupwards or downwards from the daily dose indicated.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the inhibition of the LPA receptor LPAR5. Suchcompounds may be provided in a commercial kit, for example, for use inpharmaceutical research involving the LPA receptor LPAR5. For example, acompound of the present invention can be used as a reference in an assayto compare its known activity to a compound with an unknown activity.This would ensure the experimenter that the assay was being performedproperly and provide a basis for comparison, especially if the testcompound was a derivative of the reference compound. When developing newassays or protocols, compounds according to the present invention can beused to test their effectiveness.

A compound of the formula I can also advantageously be used as anantiaggregant outside an individual. For example, an effective amount ofa compound of the invention can be contacted with a freshly drawn bloodsample to prevent aggregation of the blood sample. Further, a compoundof the formula I or its salts can be used for diagnostic purposes, forexample in vitro diagnoses, and as an auxiliary in biochemicalinvestigations. For example, a compound of the formula I can be used inan assay to identify the presence of the LPA receptor LPAR5 or toisolate the LPA receptor LPAR5 containing tissue in a substantiallypurified form. A compound of the invention can be labeled with, forexample, a radioisotope, and the labeled compound bound to the LPAreceptor LPAR5 is then detected using a routine method useful fordetecting the particular label. Thus, a compound of the formula I or asalt thereof can be used as a probe to detect the location or amount ofLPAR5 activity in vivo, in vitro or ex vivo.

Furthermore, the compounds of the formula I can be used as synthesisintermediates for the preparation of other compounds, in particular ofother pharmaceutical active ingredients, which are obtainable from thecompounds of the formula I, for example by introduction of substituentsor modification of functional groups.

The general synthetic sequences for preparing the compounds useful inthe present invention are outlined in detail in the examples given belowwhich are intended to be merely illustrative of the present inventionand not limiting it in either scope or spirit. Those with skill in theart will readily understand that known variations of the conditions andprocesses described in the examples can be used to synthesize thecompounds of the present invention.

Furthermore, the following subject-matters (1) to (12) are disclosedherein, which comprise additional compounds beside the compounds ascovered by the claim set. The additional compounds can be prepared bythe same methods as disclosed herein for the preparation of theinventive compounds.

-   (1) A compound of the formula I,

wherein

-   R¹ is selected from the series consisting of hydrogen,    (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl,    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, Ar and Ar—(C₁-C₄)-alkyl-;-   R² and R³ are independently of each other selected from the series    consisting of hydrogen, halogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, Ar, Ar—(C₁-C₄)-alkyl-,    (C₁-C₄)-alkyl-O—, (C₃-C₇)-cycloalkyl-O—,    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-O—, Ar—O— and Ar—(C₁-C₄)-alkyl-O—,-   or the groups R² and R³, in case they are bonded to adjacent ring    carbon atoms, together with the carbon atoms carrying them form a    benzene ring which is unsubstituted or substituted by one or more    identical or different substituents selected from the series    consisting of halogen, (C₁-C₄)-alkyl, cyano and (C₁-C₄)-alkyl-O—;-   R⁴ and R⁵ are independently of each other selected from the series    consisting of hydrogen, fluorine and (C₁-C₆)-alkyl,-   or the groups R⁴ and R⁵ together with the carbon atom carrying them    form a (C₃-C₇)-cycloalkane ring which is unsubstituted or    substituted by one or more identical or different substituents    selected from the series consisting of fluorine and (C₁-C₄)-alkyl;-   R¹¹, R¹², R¹³ and R¹⁴ are independently of each other selected from    the series consisting of hydrogen and (C₁-C₄)-alkyl;-   Ar is selected from the series consisting of phenyl, naphthyl and an    aromatic, 5-membered or 6-membered, monocyclic heterocycle which    comprises one or two identical or different ring heteroatoms    selected from the series consisting of N, O and S, which are all    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of halogen,    (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, cyano and (C₁-C₄)-alkyl-O—;-   V is selected from the series consisting of R¹¹—O— and R¹²—N(R¹³)—,    and in this case G and M are not present,-   or-   V is selected from the series consisting of —N(R¹⁴)—,    —N(R¹⁴)—(C₁-C₄)-alkyl-, —O— and —O—(C₁-C₄)-alkyl-, and in this case-   G is selected from the series consisting of a direct bond and    phenylene which is unsubstituted or substituted by one or more    identical or different substituents selected from the series    consisting of halogen, (C₁-C₄)-alkyl, cyano and (C₁-C₄)-alkyl-O—,    provided that G is not a direct bond if V is —N(R¹⁴)— or —O—, and-   M is selected from the series consisting of R¹¹—O—C(O)— and    R¹²—N(R¹³)—C(O)—;    wherein all alkyl groups are unsubstituted or substituted by one or    more fluorine substituents, and all cycloalkyl groups are    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of fluorine and    (C₁-C₄)-alkyl;    in any of its stereoisomeric forms or a mixture of stereoisomeric    forms in any ratio, or a pharmaceutically acceptable salt thereof.-   (2) A compound of the formula I according to subject-matter (1),    wherein-   R¹ is selected from the series consisting of hydrogen,    (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, Ar and Ar—(C₁-C₄)-alkyl-;-   R² and R³ are independently of each other selected from the series    consisting of hydrogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, Ar, Ar—(C₁-C₄)-alkyl-,    (C₁-C₄)-alkyl-O—, (C₃-C₇)-cycloalkyl-O—,    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-O—, Ar—O— and Ar—(C₁-C₄)-alkyl-O—,-   or the groups R² and R³, in case they are bonded to adjacent ring    carbon atoms, together with the carbon atoms carrying them form a    benzene ring which is unsubstituted or substituted by one or more    identical or different substituents selected from the series    consisting of halogen, (C₁-C₄)-alkyl, cyano and (C₁-C₄)-alkyl-O—;-   R⁴ and R⁵ are independently of each other selected from the series    consisting of hydrogen and (C₁-C₆)-alkyl,-   or the groups R⁴ and R⁵ together with the carbon atom carrying them    form a (C₃-C₇)-cycloalkane ring which is unsubstituted or    substituted by one or more identical or different substituents    selected from the series consisting of fluorine and (C₁-C₄)-alkyl;-   R¹¹, R¹², R¹³ and R¹⁴ are independently of each other selected from    the series consisting of hydrogen and (C₁-C₄)-alkyl;-   Ar is selected from the series consisting of phenyl, naphthyl and an    aromatic, 5-membered or 6-membered, monocyclic heterocycle which    comprises one or two identical or different ring heteroatoms    selected from the series consisting of N, O and S, which are all    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of halogen,    (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,    (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, cyano and (C₁-C₄)-alkyl-O—;-   V is R¹¹—O—, and in this case G and M are not present,-   or-   V is selected from the series consisting of —N(R¹⁴)—,    —N(R¹⁴)—(C₁-C₄)-alkyl- and —O—(C₁-C₄)-alkyl-, and in this case-   G is selected from the series consisting of a direct bond and    phenylene which is unsubstituted or substituted by one or more    identical or different substituents selected from the series    consisting of halogen, (C₁-C₄)-alkyl, cyano and (C₁-C₄)-alkyl-O—,    provided that G is not a direct bond if V is —N(R¹⁴)—, and-   M is selected from the series consisting of R¹¹—O—C(O)— and    R¹²—N(R¹³)—C(O)—;    wherein all alkyl groups are unsubstituted or substituted by one or    more fluorine substituents, and all cycloalkyl groups are    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of fluorine and    (C₁-C₄)-alkyl;    in any of its stereoisomeric forms or a mixture of stereoisomeric    forms in any ratio, or a pharmaceutically acceptable salt thereof.-   (3) A compound of the formula I according to one or more of    subject-matters (1) and (2) wherein-   R¹ is selected from the series consisting of (C₁-C₆)-alkyl,    (C₃-C₇)-cycloalkyl, Ar and Ar—(C₁-C₄)-alkyl-;-   R² and R³ are independently of each other selected from the series    consisting of hydrogen, (C₁-C₄)-alkyl, Ar, Ar—(C₁-C₄)-alkyl-,    (C₁-C₄)-alkyl-O—, (C₃-C₇)-cycloalkyl-O—, Ar—O— and    Ar—(C₁-C₄)-alkyl-O—,-   or the groups R² and R³, in case they are bonded to adjacent ring    carbon atoms, together with the carbon atoms carrying them form a    benzene ring which is unsubstituted or substituted by one or more    identical or different substituents selected from the series    consisting of halogen, (C₁-C₄)-alkyl, cyano and (C₁-C₄)-alkyl-O—;-   R⁴ and R⁵ are independently of each other selected from the series    consisting of hydrogen and (C₁-C₆)-alkyl,-   or the groups R⁴ and R⁵ together with the carbon atom carrying them    form a (C₃-C₇)-cycloalkane ring which is unsubstituted or    substituted by one or more identical or different substituents    selected from the series consisting of fluorine and (C₁-C₄)-alkyl;-   R¹¹, R¹², R¹³ and R¹⁴ are independently of each other selected from    the series consisting of hydrogen and (C₁-C₄)-alkyl;-   Ar is selected from the series consisting of phenyl, naphthyl and an    aromatic, 5-membered or 6-membered, monocyclic heterocycle which    comprises one or two identical or different ring heteroatoms    selected from the series consisting of N, O and S, which are all    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of halogen,    (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl and (C₁-C₄)-alkyl-O—;-   V is R¹¹—O—, and in this case G and M are not present,-   or-   V is selected from the series consisting of —N(R¹⁴)— and    —N(R¹⁴)—(C₁-C₄)-alkyl-, and in this case-   G is selected from the series consisting of a direct bond and    phenylene which is unsubstituted or substituted by one or more    identical or different substituents selected from the series    consisting of halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, provided    that G is not a direct bond if V is —N(R¹⁴)—, and-   M is selected from the series consisting of R¹¹—O—C(O)— and    R¹²—N(R¹³)—C(O)—;    wherein all alkyl groups are unsubstituted or substituted by one or    more fluorine substituents, and all cycloalkyl groups are    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of fluorine and    (C₁-C₄)-alkyl;    in any of its stereoisomeric forms or a mixture of stereoisomeric    forms in any ratio, or a pharmaceutically acceptable salt thereof.-   (4) A compound of the formula I according to one or more of    subject-matters 1 to 3, wherein-   R¹ is selected from the series consisting of (C₁-C₄)-alkyl, Ar and    Ar—(C₁-C₄)-alkyl-;-   R² and R³ are independently of each other selected from the series    consisting of hydrogen, (C₁-C₄)-alkyl, Ar, Ar—(C₁-C₄)-alkyl-, and    Ar—O—,-   or the groups R² and R³, in case they are bonded to adjacent ring    carbon atoms, together with the carbon atoms carrying them form a    benzene ring which is unsubstituted or substituted by one or more    identical or different substituents selected from the series    consisting of halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—;-   R⁴ and R⁵ are independently of each other selected from the series    consisting of hydrogen and (C₁-C₆)-alkyl,-   or the groups R⁴ and R⁵ together with the carbon atom carrying them    form a (C₃-C₇)-cycloalkane ring which is unsubstituted or    substituted by one or more identical or different substituents    selected from the series consisting of fluorine and (C₁-C₄)-alkyl;-   R¹¹ and R¹⁴ are independently of each other selected from the series    consisting of hydrogen and (C₁-C₄)-alkyl;-   Ar is selected from the series consisting of phenyl, naphthyl and an    aromatic, 5-membered or 6-membered, monocyclic heterocycle which    comprises one or two identical or different ring heteroatoms    selected from the series consisting of N, O and S, which are all    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of halogen,    (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl and (C₁-C₄)-alkyl-O—;-   V is R¹¹—O—, and in this case G and M are not present,-   or-   V is selected from the series consisting of —N(R¹⁴)— and    —N(R¹⁴)—(C₁-C₄)-alkyl-, and in this case-   G is selected from the series consisting of a direct bond and    phenylene which is unsubstituted or substituted by one or more    identical or different substituents selected from the series    consisting of halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, provided    that G is not a direct bond if V is —N(R¹⁴), and-   M is R¹¹—O—C(O)—;    wherein all alkyl groups are unsubstituted or substituted by one or    more fluorine substituents, and all cycloalkyl groups are    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of fluorine and    (C₁-C₄)-alkyl;    in any of its stereoisomeric forms or a mixture of stereoisomeric    forms in any ratio, or a pharmaceutically acceptable salt thereof.-   (5) A compound of the formula I according to one or more of    subject-matters (1) to (4), wherein-   R¹ is selected from the series consisting of (C₁-C₄)-alkyl, Ar and    Ar—(C₁-C₄)-alkyl-;-   R² and R³ are independently of each other selected from the series    consisting of hydrogen, (C₁-C₄)-alkyl, Ar— and Ar—O—,-   or the groups R² and R³, in case they are bonded to adjacent ring    carbon atoms, together with the carbon atoms carrying them form a    benzene ring which is unsubstituted or substituted by one or more    identical or different substituents selected from the series    consisting of halogen and (C₁-C₄)-alkyl-;-   R⁴ and R⁵ are independently of each other selected from the series    consisting of hydrogen and (C₁-C₆)-alkyl,-   or the groups R⁴ and R⁵ together with the carbon atom carrying them    form a (C₃-C₇)-cycloalkane ring which is unsubstituted or    substituted by one or more fluorine substituents;-   R¹¹ and R¹⁴ are independently of each other selected from the series    consisting of hydrogen and (C₁-C₄)-alkyl;-   Ar is selected from the series consisting of phenyl, naphthyl and an    aromatic, 5-membered or 6-membered, monocyclic heterocycle which    comprises one or two identical or different ring heteroatoms    selected from the series consisting of N, O and S, which are all    unsubstituted or substituted by one or more identical or different    substituents selected from the series consisting of halogen,    (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl and (C₁-C₄)-alkyl-O—;-   V is R¹¹—O—, and in this case G and M are not present,-   or-   V is selected from the series consisting of —N(R¹⁴)— and    —N(R¹⁴)—(C₁-C₄)-alkyl-, and in this case-   G is selected from the series consisting of a direct bond and    phenylene which is unsubstituted or substituted by one or more    identical or different substituents selected from the series    consisting of halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, provided    that G is not a direct bond if V is —N(R¹⁴), and-   M is R¹¹—O—C(O)—;    wherein all alkyl groups are unsubstituted or substituted by one or    more fluorine substituents;    in any of its stereoisomeric forms or a mixture of stereoisomeric    forms in any ratio, or a pharmaceutically acceptable salt thereof.-   (6) A compound of the formula I according to one or more of    subject-matters (1) to (5), which is selected from the series    consisting of-   2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-2-methyl-propionic    acid,-   [5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-acetic    acid,-   1-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-cyclopentanecarboxylic    acid,-   2-[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionic    acid,-   2-[1-(2-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionic    acid,-   2-[1-(4-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionic    acid,-   2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-butyric    acid,-   2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-propionic    acid,-   4-({2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-2-methyl-propionylamino}-methyl)-benzoic    acid,-   4-({2-[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionylamino}-methyl)-benzoic    acid,-   4-({2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-acetylamino}-methyl)-benzoic    acid,-   4-({2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-butyrylamino}-methyl)-benzoic    acid,-   4-({2-[1-(2-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionylamino}-methyl)-benzoic    acid,-   4-({2-[1-(4-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionylamino}-methyl)-benzoic    acid,-   4-({2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-propionylamino}-methyl)-benzoic    acid,-   4-{2-[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-propionylamino}-benzoic    acid,-   4-{2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-3-methyl-butyrylamino}-benzoic    acid,-   4-{2-[1-(4-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-propionylamino}-benzoic    acid,-   4-[2-(3-Naphthalen-2-yl-1-phenyl-1H-pyrazol-4-ylmethoxy)-propionylamino]-benzoic    acid,-   4-{2-[1-(2-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-propionylamino}-benzoic    acid,-   4-[2-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethoxy)-propionylamino]-benzoic    acid,-   4-[2-(1,3-Diphenyl-1H-pyrazol-4-ylmethoxy)-propionylamino]-benzoic    acid,-   4-{2-[1-Benzyl-3-(3-methoxy-phenyl)-1H-pyrazol-4-ylmethoxy]-propionylamino}-benzoic    acid,-   4-{2-[5-(4-Fluoro-phenoxy)-1-methyl-3-phenyl-1H-pyrazol-4-ylmethoxy]-propionylamino}-benzoic    acid,-   4-[2-(2-Methyl-2H-indazol-3-ylmethoxy)-propionylamino]-benzoic acid,-   4-{2-[3-(4-Cyclohexyl-phenyl)-1-phenyl-1H-pyrazol-4-ylmethoxy]-propionylamino}-benzoic    acid,-   4-[2-(1-Phenyl-3-thiophen-2-yl-1H-pyrazol-4-ylmethoxy)-propionylamino]-benzoic    acid, and-   4-[2-(1,5-Diphenyl-1H-pyrazol-3-ylmethoxy)-propionylamino]-benzoic    acid,    in any of its stereoisomeric forms or a mixture of stereoisomeric    forms in any ratio, or a pharmaceutically acceptable salt thereof.-   (7) A compound of the formula I or a pharmaceutically acceptable    salt thereof according to one or more of subject-matters (1) to (6)    for use as medicament.-   (8) A compound of the formula I or a pharmaceutically acceptable    salt thereof according to one or more of subject-matters (1) to (6)    for use in the treatment of a disease responsive to the inhibition    of the LPA receptor LPAR5 or the reduction or inhibition of platelet    aggregation or thrombus formation or the reduction or inhibition of    activation of mast cells or the reduction or inhibition of    activation of microglial cells.-   (9) A compound of the formula I or a pharmaceutically acceptable    salt thereof according to one or more of subject-matters (1) to (6)    for use in the treatment of thromboembolic diseases, deep vein    thrombosis, venous or arterial thromboembolism, thrombophlebitis,    coronary or cerebral arterial thrombosis, cerebral embolism, renal    embolism, pulmonary embolism, disseminated intravascular    coagulation, cardiovascular disorders, transient ischemic attacks,    strokes, acute myocardial infarction, unstable angina, chronic    stable angina, peripheral vascular disease, preeclampsia/eclampsia,    thrombotic cytopenic purpura, inflammatory disorders, hyperalgesia,    asthma, multiple sclerosis, inflammatory pain, angiogenesis,    atherothrombosis, allergic responses, or restenoses.-   (10) A compound of the formula I or a pharmaceutically acceptable    salt thereof according to one or more of subject-matters (1) to (6)    for use in the treatment of abnormal thrombus formation, acute    myocardial infarction, unstable angina, thromboembolism, acute    vessel closure associated with thrombolytic therapy or percutaneous    transluminal coronary angioplasty (PTCA), transient ischemic    attacks, stroke, intermittent claudication, bypass grafting of the    coronary or peripheral arteries, vessel luminal narrowing,    restenosis post coronary venous angioplasty, maintenance of vascular    access patency in long-term hemodialysis patients, pathologic    thrombus formation occurring in the veins of the lower extremities    following abdominal, knee or hip surgery, a risk of pulmonary    thromboembolism, or disseminated systemic intravascular    coagulatopathy occurring in vascular systems during septic shock,    viral infections or cancer.-   (11) A compound of the formula I or a pharmaceutically acceptable    salt thereof according to one or more of subject-matters (1) to (6)    for use in the treatment of inflammatory pain, asthma, angiogenesis,    demyelating diseases of the central nervous system or the peripheral    nervous system, multiple sclerosis, transverse myelitis, optic    neuritis, Devic's disease, Guillain-Barre syndrome or chronic    inflammatory demyelinating polyneuropathy.-   (12) A pharmaceutical composition comprising a compound of the    formula I or a pharmaceutically acceptable salt thereof according to    one or more of subject-matters (1) to (6), and a pharmaceutically    acceptable carrier.

EXAMPLES

When in the final step of the synthesis of a compound an acid such astrifluoroacetic acid or acetic acid was used, for example whentrifluoroacetic acid was employed to an acid-labile protecting group,for example a tBu group, or when a compound was purified bychromatography using an eluent which contained such an acid, in somecases, depending on the work-up procedure, for example the details of afreeze-drying process, the compound was obtained partially or completelyin the form of a salt of the acid used, for example in the form of theacetic acid salt, formic acid salt or trifluoroacetic acid salt orhydrochloric acid salt. Likewise starting materials or intermediatesbearing a basic center like for example a basic nitrogen were eitherobtained and used as free base or in salt form like, for example, atrifluoroacetic acid salt, a hydrobromic acid salt, a sulfuric acidsalt, or a hydrochloric acid salt. Room temperature means a temperatureof about 20° C. to 25° C.

Abbreviations

-   Acetonitrile MeCN-   tert-Butyl tBu-   N,N-Dimethylformamide DMF-   N-Ethylmorpholine NEM-   Tetrahydrofuran THF-   Trifluoroacetic acid TFA

Example 12-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-2-methyl-propionicacid

(i)[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl]-methanol

To a solution of 5 g of5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid in 130 ml of THF, were added dropwise 40 ml of a 1M solution ofborane in THF at room temperature. Then the reaction mixture was heatedto reflux for 10 h. The reaction mixture was cooled to room temperatureand 20 ml of methanol were carefully added. The solvents were removedunder reduced pressure and the residue was dissolved in ethyl acetate.The organic layer was washed with 1 M hydrochloric acid, saturatedsodium chloride solution and saturated sodium hydrogen carbonatesolution. The combined organic layers were dried over MgSO₄, filteredand concentrated under reduced pressure. The product was obtained as awhite solid and used without further purification.

Yield: 4.6 g.

(ii)2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-2-methyl-propionicacid ethyl ester

To a solution of 1.6 g of[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl]-methanolin 15 ml of DMF were added 870 mg of sodium hydride (60% in mineral oil)at room temperature. After 15 min 1.6 g of tetrabutylammonium iodide and3.4 g of 2-Bromo-2-methyl-propionic acid ethyl ester were added and thereaction mixture was stirred for 16 h at room temperature. Afterdilution with saturated aqueous sodium hydrogen carbonate solution thereaction mixture was filtered through a chem Elut® cartridge by elutingwith ethyl acetate The solvents were removed under reduced pressure andthe crude product was purified by chromatography on silica gel elutingwith a gradient of n-heptane/ethyl acetate. The fractions containing theproduct were combined and the solvent evaporated under reduced pressure.Yield: 1.3 g.

(iii)2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-2-methyl-propionicacid

To a solution of 735 mg of2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-2-methyl-propionicacid ethyl ester in 10 ml THF was added a solution of 51 mg of LiOH in 1ml water at room temperature. After 16 h the mixture was brought to pH 2by addition of 1 M hydrochloric acid. The reaction mixture wasconcentrated under reduced pressure and the aqueous layer was extractedwith dichloromethane. The combined organic phases were dried over MgSO₄and the solvents were removed under reduced pressure. The residue waspurified by preparative HPLC (C18 reverse phase column, elution with awater/MeCN gradient with 0.1% TFA). The fractions containing the productwere evaporated and lyophilized to yield a white solid. Yield: 677 mg.

MS (ES-): m/e=451, chloro pattern.

Example 2[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-aceticacid

The title compound was prepared analogously as described in example 1.

MS (ES-): m/e=423, chloro pattern.

Example 31-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-cyclopentanecarboxylicacid

The title compound was prepared analogously as described in example 1.

MS (ES-): m/e=477, chloro pattern.

Example 42-[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionicacid

(i) Lithium3-ethoxycarbonyl-2-methyl-3-oxo-1-(4-trifluoromethyl-phenyl)-propan-1-olate

To a solution of 118 ml of lithium bis(trimethylsilyl)amide (LithiumHexamethyldisilazide; 0.9 M in methylcyclohexane) was added dropwiseover 15 min, 20 g of 1-(4-Trifluoromethyl-phenyl)-propan-1-one in 51 mlmethylcyclohexane at while maintaining the reaction mixture at 15-25° C.After stirring for 2 h, 15 ml of diethyl oxalate were added dropwiseover 30 min and the reaction mixture was stirred for 16 h. Then, theprecipitated product was collected by filtration and washed withn-heptane. The isolated crude product was used in the next reaction stepafter drying in vacuo. Yield: 19 g.

(ii)1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylicacid

A solution of 10 g of Lithium3-ethoxycarbonyl-2-methyl-3-oxo-1-(4-trifluoromethyl-phenyl)-propan-1-olate,6.9 g of (2,4-Dichloro-phenyl)-hydrazine hydrochloride and 74 ml ofsulfuric acid (50%) in 184 ml of ethanol was heated to reflux for 7 h.After cooling to room temperature the organic solvents were removedunder reduced pressure and the residue was diluted with 100 ml of waterand extracted with ethyl acetate. The combined organic layers were driedover MgSO₄ and the solvent was removed under reduced pressure. Theresidue was dissolved in 100 ml THF and a solution of 1.4 g of LiOH in20 ml water was added at room temperature. The reaction mixture washeated to 60° C. for 7 h. Then, after cooling to room temperature themixture was acidified to pH 1 by addition of half-concentratedhydrochloric acid. The precipitating product was collected by filtrationand washed with water. The residue was codistilled twice withdichloromethane and twice with toluene. The isolated crude product wasused in the next reaction step. Yield: 13 g.

(iii)[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-yl]-methanol

To a solution of 4.5 g of1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylicacid in 30 ml of THF, were added dropwise 43 ml of a 1M solution ofborane in THF at room temperature. Then the reaction mixture was heatedto reflux for 10 h. The reaction mixture was cooled to room temperatureand 20 ml of methanol were carefully added. The solvents were removedunder reduced pressure and the residue was dissolved in ethyl acetate.The organic layer was washed with 1 M hydrochloric acid, saturatedsodium chloride solution and saturated sodium hydrogen carbonatesolution. The organic layers were combined and dried over MgSO₄,filtered and concentrated under reduced pressure. The product wasobtained as a white solid and was used without further purification.

Yield: 4.3 g.

(iv)2-[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionicacid ethyl ester

To a solution of 2 g of[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-yl]-methanolin 15 ml of DMF were added 997 mg of sodium hydride (60% in mineral oil)at room temperature. After 15 min 1.8 g of tetrabutylammonium iodide and2.9 g of 2-Bromo-2-methyl-propionic acid ethyl ester were added and thereaction mixture was stirred for 16 h at room temperature. Afterdilution with saturated aqueous sodium hydrogen carbonate solution thereaction mixture was filtered through a chem Elut® cartridge by elutingwith ethyl acetate. The solvents were removed under reduced pressure andthe crude product was purified by chromatography on silica gel elutingwith a gradient of n-heptane/ethyl acetate. The fractions containing theproduct were combined and the solvent evaporated under reduced pressure.Yield: 1.3 g.

(v)2-[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionicacid

To a solution of 1 g of2-[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionicacid ethyl ester in 6 ml THF was added a solution of 232 mg of LiOH in 1ml water at room temperature. After 16 h the mixture was brought to pH 2by addition of 1 M hydrochloric acid. The reaction mixture wasconcentrated under reduced pressure and the aqueous layer was extractedwith dichloromethane. The combined organic phases were dried over MgSO₄and the solvents were removed under reduced pressure. The residue waspurified by preparative HPLC (C18 reverse phase column, elution with awater/MeCN gradient with 0.1% TFA). The fractions containing the productwere evaporated and lyophilized to yield a yellow solid. Yield: 634 mg.

MS (ES-): m/e=485, chloro pattern.

Example 52-[1-(2-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionicacid

The title compound was prepared analogously as described in example 5.

MS (ES-): m/e=451, chloro pattern.

Example 62-[1-(4-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionicacid

The title compound was prepared analogously as described in example 5.

MS (ES-): m/e=451, chloro pattern.

Example 72-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-butyricacid

The title compound was prepared analogously as described in example 5.

MS (ES-): m/e=452, chloro pattern.

Example 82-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-propionicacid

The title compound was prepared analogously as described in example 5.

MS (ES-): m/e=439, chloro pattern.

Example 94-({2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-2-methyl-propionylamino}-methyl)-benzoicacid

(i)[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl]-methanol

To a solution of 5 g of5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid in 130 ml of THF, were added dropwise 40 ml of a 1M solution ofborane in THF at room temperature. Then, the reaction mixture was heatedto reflux for 10 h. The reaction mixture was cooled to room temperatureand 20 ml of methanol were carefully added. The solvents were removedunder reduced pressure and the residue was dissolved in ethyl acetate.The organic layer was washed with 1 M hydrochloric acid saturated sodiumchloride solution and saturated sodium hydrogen carbonate solution. Thecombined organic layers were dried over MgSO₄, filtered and concentratedunder reduced pressure. The product was obtained as a white solid andwas used without further purification. Yield: 4.6 g.

(ii)2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-2-methyl-propionicacid ethyl ester

To a solution of 1.6 g of[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl]-methanolin 15 ml of DMF were added 870 mg of sodium hydride (60% in mineral oil)at room temperature. After 15 min, 1.6 g of tetrabutylammonium iodideand 3.4 g of 2-Bromo-2-methyl-propionic acid ethyl ester were added andthe reaction mixture was stirred for 16 h at room temperature. Afterdilution with saturated aqueous sodium hydrogen carbonate solution thereaction mixture was filtered through a chem Elut® cartridge by elutingwith ethyl acetate. The solvents were removed under reduced pressure andthe crude product was purified by chromatography on silica gel elutingwith a gradient of n-heptane/ethyl acetate. The fractions containing theproduct were combined and the solvent evaporated under reduced pressure.Yield: 1.3 g.

(iii)2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-2-methyl-propionicacid

To a solution of 1.3 g of2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-2-methyl-propionicacid ethyl ester in 10 ml THF was added a solution of 130 mg of LiOH in3 ml water at room temperature. After 5 h the mixture was brought to pH2 by addition of 1 M hydrochloric acid. The reaction mixture wasconcentrated under reduced pressure and the aqueous layer was extractedwith dichloromethane. The combined organic phases were dried over MgSO₄and the solvents were removed under reduced pressure. The isolated crudeproduct was used in the next reaction step. Yield: 1.5 g.

(iv)4-({2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-2-methyl-propionylamino}-methyl)-benzoicacid

To a solution of 710 mg of2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-2-methyl-propionicacid in 5 ml of DMF, 360 mg ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), 345mg of pentafluorophenol and 392 mg of NEM were added and the reactionmixture was stirred for 3 h at room temperature. Then, 353 mg of4-Aminomethyl-benzoic acid and 540 mg of NEM in 5 ml of DMF were added.After 16 h the reaction mixture was diluted with water and filteredthrough a chem Elut® cartridge by eluting with ethyl acetate. Thesolvents were removed under reduced pressure and the residue waspurified by preparative HPLC (C18 reverse phase column, elution with awater/MeCN gradient with 0.1% TFA). The fractions containing the productwere evaporated and lyophilized to yield a white solid. Yield: 288 mg.

MS (ES-): m/e=586, chloro pattern.

Example 104-({2-[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionylamino}-methyl)-benzoicacid

(i) Lithium3-ethoxycarbonyl-2-methyl-3-oxo-1-(4-trifluoromethyl-phenyl)-propan-1-olate

To a solution of 118 ml of lithium bis(trimethylsilyl)amide (LithiumHexamethyldisilazide; 0.9 M in methylcyclohexane) was added dropwiseover 15 min 20 g of 1-(4-Trifluoromethyl-phenyl)-propan-1-one in 51 mlmethylcyclohexane at while maintaining the reaction mixture at 15-25° C.After stirring for 2 h, 15 ml of diethyl oxalate were added dropwiseover 30 min and the reaction mixture was stirred for 16 h. Then, theprecipitated product was collected by filtration and washed withn-heptane. The isolated crude product was used in the next reaction stepafter drying in vacuo. Yield: 19 g.

(ii)1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid

A solution of 10 g of Lithium3-ethoxycarbonyl-2-methyl-3-oxo-1-(4-trifluoromethyl-phenyl)-propan-1-olate,6.9 g of (2,4-Dichloro-phenyl)-hydrazine hydrochloride and 74 ml ofsulfuric acid (50%) in 184 ml of ethanol was heated to reflux for 7 h.After cooling to room temperature the organic solvents were removedunder reduced pressure and the residue was diluted with 100 ml of waterand extracted with ethyl acetate. The combined organic layers were driedover MgSO₄ and the solvent was removed under reduced pressure. Theresidue was dissolved in 100 ml THF and a solution of 1.4 g of LiOH in20 ml water was added at room temperature. The reaction mixture washeated to 60° C. for 7 h. Then, after cooling to room temperature themixture was acidified to pH 1 by addition of half-concentratedhydrochloric acid.

The precipitating product was collected by filtration and washed withwater. The residue was codistilled twice with dichloromethane and twicewith toluene. The isolated crude product was used in the next reactionstep. Yield: 13 g.

(iii)[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-yl]-methanol

To a solution of 4.5 g of1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylicacid in 30 ml of THF, were added dropwise 43 ml of a 1M solution ofborane in THF at room temperature. Then the reaction mixture was heatedto reflux for 10 h. The reaction mixture was cooled to room temperatureand 20 ml of methanol were carefully added. The solvents were removedunder reduced pressure and the residue was dissolved in ethyl acetate.The organic layer was washed with 1 M hydrochloric acid, saturatedsodium chloride solution and saturated sodium hydrogen carbonatesolution. The combined organic layers were dried over MgSO₄, filteredand concentrated under reduced pressure. The product was obtained as awhite solid and used without further purification. Yield: 4.3 g.

(iv)2-[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionicacid ethyl ester

To a solution of 2 g of[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-yl]-methanolin 12 ml of DMF were added 997 mg of sodium hydride

(60% in mineral oil) at room temperature. After 15 min, 1.8 g oftetrabutylammonium iodide and 2.9 g of 2-Bromo-2-methyl-propionic acidethyl ester were added and the reaction mixture was stirred for 16 h atroom temperature. After dilution with saturated aqueous sodium hydrogencarbonate solution the reaction mixture was filtered through a chemElut® cartridge by eluting with ethyl acetate. The solvents were removedunder reduced pressure and the crude product was purified bychromatography on silica gel eluting with a gradient of n-heptane/ethylacetate. The fractions containing the product were combined and thesolvent evaporated under reduced pressure. Yield: 735 mg.

(v)2-[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionicacid

To a solution of 735 mg of2-[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionicacid ethyl ester in 5 ml THF was added a solution of 51 mg of LiOH in 1ml water at room temperature. After 5 h the mixture was brought to pH 2by addition of 1 M hydrochloric acid. The reaction mixture wasconcentrated under reduced pressure and the aqueous layer was extractedwith dichloromethane. The combined organic phases were dried over MgSO₄and the solvents were removed under reduced pressure. The isolated crudeproduct was used in the next reaction step. Yield: 677 mg.

(vi)4-({2-[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionylamino}-methyl)-benzoicacid

To a solution of 600 mg of2-[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionicacid in 9 ml of DMF, 283 mg ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), 271mg of pentafluorophenol and 300 mg of NEM was added and the reactionmixture was stirred for 3 h at room temperature. Then, 278 mg of4-Aminomethyl-benzoic acid and 424 mg of NEM in 10 ml of DMF were added.After 16 h the reaction mixture was diluted with water and filteredthrough a chem Elut® cartridge by eluting with ethyl acetate. Thesolvents were removed under reduced pressure and the residue waspurified by preparative HPLC (C18 reverse phase column, elution with awater/MeCN gradient with 0.1% TFA). The fractions containing the productwere evaporated and lyophilized to yield a white solid. Yield: 204 mg.

MS (ES-): m/e=618, chloro pattern.

Example 114-({2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-acetylamino}-methyl)-benzoicacid

The title compound was prepared analogously as described in example 11.

MS (ES-): m/e=556, chloro pattern.

Example 124-({2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-butyrylamino}-methyl)-benzoicacid

The title compound was prepared analogously as described in example 11.

MS (ES-): m/e=586, chloro pattern.

Example 134-({2-[1-(2-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionylamino}-methyl)-benzoicacid

The title compound was prepared analogously as described in example 11.

MS (ES-): m/e=584, chloro pattern.

Example 144-({2-[1-(4-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionylamino}-methyl)-benzoicacid

The title compound was prepared analogously as described in example 11.

MS (ES-): m/e=584, chloro pattern.

Example 154-({2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-propionylamino}-methyl)-benzoicacid

The title compound was prepared analogously as described in example 11.

MS (ES-): m/e=570, chloro pattern.

Example 164-{2-[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-propionylamino}-benzoicacid

(i) 4-(2-Bromo-propionylamino)-benzoic acid methyl ester

To a solution of 1.1 g of 4-Amino-benzoic acid methyl ester in 17 ml oftoluene were added 2.2 ml of pyridine and 1.5 g of 2-Bromo-propionylbromide at room temperature. After 16 h the reaction mixture was dilutedwith water and filtered through a chem Elut® cartridge by eluting withethyl acetate. The solvents were removed under reduced pressure and thecrude product was purified by chromatography on silica gel eluting witha gradient of n-heptane/ethyl acetate. The fractions containing theproduct were combined and the solvent evaporated under reduced pressure.Yield: 2 g.

(ii)4-{2-[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-propionylamino}-benzoicacid

To a solution of 100 mg of[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-yl]-methanolin 3 ml of DMF were added 54 mg of sodium hydride (60% in mineral oil)at room temperature. After 15 min, 100 mg of tetrabutylammonium iodideand 117 mg of 4-(2-Bromo-propionylamino)-benzoic acid methyl ester wereadded and the reaction mixture was heated to 80° C. for 8 h. Aftercooling to room temperature and dilution with 1 M aqueous hydrochloricacid the reaction mixture was filtered through a chem Elut® cartridge byeluting with ethyl acetate. The solvents were removed under reducedpressure and the residue was purified by preparative HPLC (C18 reversephase column, elution with a water/MeCN gradient with 0.1% TFA). Thefractions containing the product were evaporated and lyophilized toyield a white solid. Yield: 24 mg.

MS (ES-): m/e=590, chloro pattern.

Example 174-{2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-3-methyl-butyrylamino}-benzoicacid

The title compound was prepared analogously as described in example 16.

MS (ES-): m/e=584, chloro pattern.

Example 184-{2-[1-(4-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-propionylamino}-benzoicacid

The title compound was prepared analogously as described in example 16.

MS (ES-): m/e=556, chloro pattern.

Example 194-[2-(3-Naphthalen-2-yl-1-phenyl-1H-pyrazol-4-ylmethoxy)-propionylamino]-benzoicacid

The title compound was prepared analogously as described in example 16.

MS (ES-): m/e=590.

Example 204-{2-[1-(2-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-propionylamino}-benzoicacid

The title compound was prepared analogously as described in example 16.

MS (ES-): m/e=556, chloro pattern.

Example 214-[2-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethoxy)-propionylamino]-benzoicacid

The title compound was prepared analogously as described in example 16.

MS (ES-): m/e=392.

Example 224-[2-(1,3-Diphenyl-1H-pyrazol-4-ylmethoxy)-propionylamino]-benzoic acid

The title compound was prepared analogously as described in example 16.

MS (ES-): m/e=440.

Example 234-{2-[1-Benzyl-3-(3-methoxy-phenyl)-1H-pyrazol-4-ylmethoxy]-propionylamino}-benzoicacid

The title compound was prepared analogously as described in example 16.

MS (ES-): m/e=484.

Example 244-{2-[5-(4-Fluoro-phenoxy)-1-methyl-3-phenyl-1H-pyrazol-4-ylmethoxy]-propionylamino}-benzoicacid

The title compound was prepared analogously as described in example 16.

MS (ES-): m/e=488.

Example 254-[2-(2-Methyl-2H-indazol-3-ylmethoxy)-propionylamino]-benzoic acid

The title compound was prepared analogously as described in example 16.

MS (ES-): m/e=352.

Example 264-{2-[3-(4-Cyclohexyl-phenyl)-1-phenyl-1H-pyrazol-4-ylmethoxy]-propionylamino}-benzoicacid

The title compound was prepared analogously as described in example 16.

MS (ES-): m/e=522.

Example 274-[2-(1-Phenyl-3-thiophen-2-yl-1H-pyrazol-4-ylmethoxy)-propionylamino]-benzoicacid

The title compound was prepared analogously as described in example 16.

MS (ES-): m/e=446.

Example 284-[2-(1,5-Diphenyl-1H-pyrazol-3-ylmethoxy)-propionylamino]-benzoic acid

The title compound was prepared analogously as described in example 16.

MS (ES-): m/e=440.

Pharmacological Testing

The ability of the compounds of the formula Ito inhibit or bind the LPAreceptor LPAR5 can be assessed by determining the effect on cellularfunction. This ability of such compounds was evaluated in a plateletaggregation assay such as the Born method using single cuvettes and formast cells and microglia cells with the Fluorometric Imaging PlateReader (FLIPR) assay by Molecular Devices Inc.

A) Aggregation Assay for Washed Human Blood Platelets (Thrombocytes)

Whole blood was collected from healthy volunteers using 3×20 ml syringescontaining each 1/10 volume of buffered citrate. The anticoagulatedwhole blood was transferred into 50 ml polypropylene conical tubes (30ml per tube). The tubes were centrifuged for 10 minutes at 150×g at roomtemperature without using the centrifuge brake. This procedure resultsin a lower phase of cellular components and a supernatant (upper phase)of platelet rich plasma (PRP). The PRP phase was collected from eachtube and pooled for each donor. To avoid carry over of cellularcomponents following first centrifugation, approximately 5 ml of PRP wasleft in the tube. The platelet concentration was determined using a ABXMicros 60 counter. The PRP phase was transferred to a new 50 ml tube.After 10 minutes standing at room temperature, 1 μl PGI₂ (1 mM inTris-HCl/pH 8.8) and 180 μl ACD/A were added per ml PRP. The PRP wasthen transferred to new 10 ml tube and centrifuged for 10 minutes at500×g. After centrifugation a cellular pellet is visible at the bottomof the tube. The supernatant was carefully discarded and the cellularpellet, consisting of human blood platelets was then dissolved in 10 mlbuffer T (buffer T composition: 145 mM NaCl, 5 mM KCl, 0.1 mM MgCl2×6H₂O, 15 mM HEPES, 5.5 mM glucose, pH 7.4). Platelet concentration inthis solution was determined and buffer T was added to obtain a finalconcentration of 3.5×10⁵ platelets per ml.

After 10 minutes at room temperature, 1 μl PGI₂ per ml platelet solutionwas added and distributed into new 10 ml tubes. After a centrifugationstep, 10 minutes at 500×g, supernatant was discarded and the plateletswere resuspended in buffer T to a final concentration of 3.5×10⁵platelets per ml buffer T. Before use, platelet-containing bufferequilibrated for 30 minutes at room temperature. The human plateletaggregation assay was performed in single use cuvettes using thePlatelet Aggregation Profiler® (PAP-4 or -8E, BIO/DATA Corporation). Fora single experiment, 320 μl of platelet solution were transferred intoan assay cuvette, 20 μl of calcium citrate solution (10 mM in H₂O) and20 μl of fibrinogen solution (20 mg/ml H₂O) were added. The aggregationassay was performed in the assay cuvette at 37° C. and with 1.200 rpmstirring. To determine the EC₅₀, eight assay cuvettes were loaded asdescribed above with different concentrations of LPA. Aggregation wasmeasured over 6 minutes at 37° C. with 1200 rpm (revolutions per minute)stirring. Results of the assay are expressed as % activation, and arecalculated using maximum aggregation (T_(max)) or area under curve (AUC)of the absorbance over 6 minutes. The inhibitory effect (IC₅₀) of thetest compounds was determined as the reduction of the maximalaggregation. Test compound was added prior starting the experiment withan incubation time of the test compound of 5 minutes at 37° C. with 1200rpm stirring. The IC₅₀ data of the above described platelet aggregationassay using human washed platelets for exemplary compounds of thepresent invention are shown in Table 1.

TABLE 1 Example IC₅₀ (μM) 7 4.7 8 4.1 9 2.9 12 4.3 15 6.5 17 15.9

B) Use of the Fluorometric Imaging Plate Reader (FLIPR) Assay for theDetermination of Intracellular Ca²⁺ Release in Human Mast Cell LineHMC-1 and the Murine Microglia cell line BV-2

The ability of the compounds of the formula Ito inhibit or bind the LPAreceptor LPAR5 can be assessed by determining the intracellular Ca²⁺release in human or animal cells. For the analysis of activatingpotential of LPA and the inhibitory effects of compounds of the formulaI two cell lines were used with high LPAR5 expression, the human mastcell line HMC-1 and the murine microglia cell line BV-2 (FIGS. 1 and 2).For the FLIPR assay using human mast cells in a 96-well-format, HMC-1suspension cells from flask culture were harvested, resuspended andcounted. 14×10⁶ HMC-1 cells were transferred into a new 50 ml tube,centrifuged for 3 minutes at 540×g. The resulting cell pellet at thebottom of the tube was resuspended with 15 ml loading buffer (loadingbuffer contained HBSS buffer (pH 7.4), 0.1% BSA (bovine serum albumin),2 μM FLUO-4 dye; HBSS buffer (pH 7.4) contained 1×HBSS, 20 mM HEPES,0.01% Pluronic F-127, 2.5 mM Probenicid).

Cells in loading buffer were incubated for 45-60 minutes at 37° C. Afterincubation cells were centrifuged for 3 minutes at 540×g and resuspendedwith 21 ml of HBSS buffer (pH 7.4). Each well of a poly-D-lysine coated96-well-plate was filled with 150 μl cell solution, an equivalent of 100000 cells/well. The 96-well-plate was centifuged for 2 minutes at 100×g(without brake) prior a recovery time of 30 minutes at 37° C. After thisprocedure cells were stimulated with LPA (in HBSS pH 7.4 and 0.1% BSA)to determine the EC₅₀ of LPA in HMC-1 cells. For the determination ofthe inhibitory effect of compounds of the formula I, test compounds wereadded to the cells in the 96-well-plate 10 minutes prior the addition ofLPA. Results of the assay are expressed as % activation, and arecalculated using maximum peak of activation (A_(max)). The IC₅₀ data ofthe above described FLIPR assay using human mast cell line HMC-1 forexemplary compounds of the present invention are shown in Table 2.Adherent BV-2 cells were seeded onto poly-D-lysine coated 96-well-plates(100000 cells/well) the day before performing the FLIPR assay. Thedensity of the cells in the 96-well-plate at the day of the FLIPR assayshould be 90%. After aspiration of the culture media, BV-2 cells wereincubated for 30 minutes at 37° C. with loading buffer and recovered in150 μl HBSS buffer for 30 minutes at 37° C. After this procedure cellswere stimulated with LPA (in HBSS pH 7.4 and 0.1% BSA) to determine theEC₅₀ of LPA in BV-2 cells. For the determination of the inhibitoryeffect of compounds of the formula I, test compounds were added to thecells in the 96-well-plate 10 minutes prior the addition of LPA. TheIC₅₀ data of the above described FLIPR assay using the murine microgliacell line BV-2 for exemplary compounds of the present invention areshown in Table 3.

TABLE 2 Example IC₅₀ (μM) 1 8.3 3 8.8 4 6.6 7 11.4 8 6.3 9 1.3 10 0.0311 8.6 12 6.3 13 1.3 14 3.4 15 8.8 16 4.1 17 4.2 18 3.8 20 5.2 22 16

TABLE 3 Example IC₅₀ (μM) 9 1.8 10 0.2

The invention claimed is:
 1. A compound of the formula I,

in any of its stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, or a pharmaceutically acceptable salt thereof, wherein R¹is selected from the series consisting of hydrogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, Ar andAr—(C₁-C₄)-alkyl-; R² and R³ are independently of each other selectedfrom the series consisting of hydrogen, halogen, (C₁-C₄)-alkyl,(C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, Ar,Ar—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—, (C₃-C₇)-cycloalkyl-O—,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-O—, Ar—O—and Ar—(C₁-C₄)-alkyl-O—; R⁴and R⁵ are independently of each other selected from the seriesconsisting of hydrogen, fluorine and (C₁-C₆)-alkyl; or the groups R⁴ andR⁵ together with the carbon atom carrying them form a(C₃-C₇)-cycloalkane ring which is unsubstituted or substituted by one ormore identical or different substituents selected from the seriesconsisting of fluorine and (C₁-C₄)-alkyl; R¹¹, R¹², R¹³ and R¹⁴ areindependently of each other selected from the series consisting ofhydrogen and (C₁-C₄)-alkyl; Ar is selected from the series consisting ofphenyl, naphthyl and an aromatic, 5-membered or 6-membered, monocyclicheterocycle which comprises one or two identical or different ringheteroatoms selected from the series consisting of N, O and S, which areall unsubstituted or substituted by one or more identical or differentsubstituents selected from the series consisting of halogen,(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-,cyano and (C₁-C₄)-alkyl-O—; V is selected from the series consisting ofR¹²—N(R¹³)—, and in this case G and M are not present, or V is selectedfrom the series consisting of —N(R¹⁴)—, —N(R¹⁴)—(C₁-C₄)-alkyl-, —O—and—O—(C₁-C₄)-alkyl-, and in this case G is selected from the seriesconsisting of a direct bond and phenylene which is unsubstituted orsubstituted by one or more identical or different substituents selectedfrom the series consisting of halogen, (C₁-C₄)-alkyl, cyano and(C₁-C₄)-alkyl-O—, provided that G is not a direct bond if V is—N(R¹⁴)—or —O—, and M is selected from the series consisting of R¹¹—O—C(O)—and R¹²—N(R¹³)—C(O)—; wherein all alkyl groups are unsubstitutedor substituted by one or more fluorine substituents, and all cycloalkylgroups are unsubstituted or substituted by one or more identical ordifferent substituents selected from the series consisting of fluorineand (C₁-C₄)-alkyl; provided that that the compound is not:4-({2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxyl]-2-methyl-propionylamino}-methyl)-benzoic acid;4-({2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxyl]-acetylamino}-methyl)-benzoicacid;4-({2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-butyrylamino}-methyl)-benzoicacid;4-({2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-propionylamino}-methyl)-benzoicacid; and provided that when R¹ is 2,4-dichlorophenyl, R² and R⁴ aremethyl, R³ is 4-methylphenyl, 4-trifluoromethoxyphenyl or2,4-dichlorophenyl , V is —NH—CH₂—, G is phenyl and M is —COOH, R⁵ isnot methyl; and provided that when R¹ is 2,4-dichlorophenyl, R² and R⁴are methyl, R³ is 4-trifluoromethylphenyl or 4-trifluoromethoxyphenyl, Vis —NH₂, R⁵ is not methyl; and provided that when R¹ is4-trifluoromethoxyphenyl, R² and R⁴ are methyl, R³ is2,4-dichlorophenyl, V is —NH₂—CH₂—, G is phenyl and M is —COOH, R⁵ isnot methyl.
 2. A compound of the formula I according to claim 1, whereinR¹ is selected from the series consisting of hydrogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, Ar and Ar—(C₁-C₄)-alkyl-; R² and R³ areindependently of each other selected from the series consisting ofhydrogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, Ar, Ar—(C₁-C₄)-alkyl-,(C₁-C₄)-alkyl-O—, (C₃-C₇)-cycloalkyl-O—,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-O—, Ar—O—and Ar—(C₁-C₄)-alkyl-O—; R⁴and R⁵ are independently of each other selected from the seriesconsisting of hydrogen and (C₁-C₆)-alkyl; or the groups R⁴ and R⁵together with the carbon atom carrying them form a (C₃-C₇) -cycloalkanering which is unsubstituted or substituted by one or more identical ordifferent substituents selected from the series consisting of fluorineand (C₁-C₄)-alkyl; R¹¹, R¹², R¹³ and R¹⁴ are independently of each otherselected from the series consisting of hydrogen and (C₁-C₄)-alkyl; Ar isselected from the series consisting of phenyl, naphthyl and an aromatic,5-membered or 6-membered, monocyclic heterocycle which comprises one ortwo identical or different ring heteroatoms selected from the seriesconsisting of N, O and S, which are all unsubstituted or substituted byone or more identical or different substituents selected from the seriesconsisting of halogen, (C₁-C₄)-alkyl, (C₃-C₇) -cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, cyano and (C₁-C₄)-alkyl-O—; V isselected from the series consisting of —N(R¹⁴)—, —N(R¹⁴)—(C₁-C₄)-alkyl-and —O—(C₁-C₄)-alkyl; G is selected from the series consisting of adirect bond and phenylene which is unsubstituted or substituted by oneor more identical or different substituents selected from the seriesconsisting of halogen, (C₁-C₄)-alkyl, cyano and (C₁-C₄)-alkyl-O—,provided that G is not a direct bond if V is —N(R¹⁴)—; and M is selectedfrom the series consisting of R¹¹—O—C(O)— and R¹²—N(R¹³)—C(O)—; whereinall alkyl groups are unsubstituted or substituted by one or morefluorine substituents, and all cycloalkyl groups are unsubstituted orsubstituted by one or more identical or different substituents selectedfrom the series consisting of fluorine and (C₁-C₄)-alkyl; in any of itsstereoisomeric forms or a mixture of stereoisomeric forms in any ratio,or a pharmaceutically acceptable salt thereof.
 3. A compound of theformula I according to claim 1, wherein R¹ is selected from the seriesconsisting of (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, Ar andAr—(C₁-C₄)-alkyl-; R² and R³ are independently of each other selectedfrom the series consisting of hydrogen, (C₁-C₄)-alkyl, Ar,Ar—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—, (C₃-C₇)-cycloalkyl -O—, Ar—O— andAr—(C₁-C₄)-alkyl-O—; R⁴ and R⁵ are independently of each other selectedfrom the series consisting of hydrogen and (C₁-C₆)-alkyl; or the groupsR⁴ and R⁵ together with the carbon atom carrying them form a (C₃-C₇)-cycloalkane ring which is unsubstituted or substituted by one or moreidentical or different substituents selected from the series consistingof fluorine and (C₁-C₄)-alkyl; R¹¹, R¹², R¹³ and R¹⁴ are independentlyof each other selected from the series consisting of hydrogen and(C₁-C₄)-alkyl; Ar is selected from the series consisting of phenyl,naphthyl and an aromatic, 5-membered or 6-membered, monocyclicheterocycle which comprises one or two identical or different ringheteroatoms selected from the series consisting of N, O and S, which areall unsubstituted or substituted by one or more identical or differentsubstituents selected from the series consisting of halogen,(C₁-C₄)-alkyl, (C₃-C₇) -cycloalkyl and (C₁-C₄)-alkyl-O—; V is selectedfrom the series consisting of —N(R¹⁴)— and —N(R¹⁴)—(C₁-C₄)-alkyl-; G isselected from the series consisting of a direct bond and phenylene whichis unsubstituted or substituted by one or more identical or differentsubstituents selected from the series consisting of halogen,(C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, provided that G is not a direct bondif V is —N(R¹⁴)—; and M is selected from the series consisting ofR¹¹—O—C(O)— and R¹²—N(R¹³)—C(O)—; wherein all alkyl groups areunsubstituted or substituted by one or more fluorine substituents, andall cycloalkyl groups are unsubstituted or substituted by one or moreidentical or different substituents selected from the series consistingof fluorine and (C₁-C₄)-alkyl; in any of its stereoisomeric forms or amixture of stereoisomeric forms in any ratio, or a pharmaceuticallyacceptable salt thereof.
 4. A compound of the formula I according toclaim 1, wherein R¹ is selected from the series consisting of(C₁-C₄)-alkyl, Ar and Ar—(C₁-C₄)-alkyl-; R² and R³ are independently ofeach other selected from the series consisting of hydrogen,(C₁-C₄)-alkyl, Ar, Ar—(C₁-C₄)-alkyl-, and Ar—O—; R⁴ and R⁵ areindependently of each other selected from the series consisting ofhydrogen and (C₁-C₆)-alkyl; or the groups R⁴ and R⁵ together with thecarbon atom carrying them form a (C₃-C₇) -cycloalkane ring which isunsubstituted or substituted by one or more identical or differentsubstituents selected from the series consisting of fluorine and(C₁-C₄)-alkyl; R¹¹ and R¹⁴ are independently of each other selected fromthe series consisting of hydrogen and (C₁-C₄)-alkyl; Ar is selected fromthe series consisting of phenyl, naphthyl and an aromatic, 5-membered or6-membered, monocyclic heterocycle which comprises one or two identicalor different ring heteroatoms selected from the series consisting of N,O and S, which are all unsubstituted or substituted by one or moreidentical or different substituents selected from the series consistingof halogen, (C₁-C₄)-alkyl, (C₃-C₇) -cycloalkyl and (C₁-C₄)-alkyl-O—; Vis selected from the series consisting of —N(R¹⁴)— and—N(R¹⁴)—(C₁-C₄)-alkyl-; and G is selected from the series consisting ofa direct bond and phenylene which is unsubstituted or substituted by oneor more identical or different substituents selected from the seriesconsisting of halogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, provided thatG is not a direct bond if V is —N(R¹⁴), and M is R¹¹—O—C(O)—; whereinall alkyl groups are unsubstituted or substituted by one or morefluorine substituents, and all cycloalkyl groups are unsubstituted orsubstituted by one or more identical or different substituents selectedfrom the series consisting of fluorine and (C₁-C₄)-alkyl; in any of itsstereoisomeric forms or a mixture of stereoisomeric forms in any ratio,or a pharmaceutically acceptable salt thereof.
 5. A compound of theformula I according to claim 1, wherein R¹ is selected from the seriesconsisting of (C₁-C₄)-alkyl, Ar and Ar—(C₁-C₄)-alkyl-; R² and R³ areindependently of each other selected from the series consisting ofhydrogen, (C₁-C₄)-alkyl, Ar—and Ar—O—; R⁴ and R⁵ are independently ofeach other selected from the series consisting of hydrogen and(C₁-C₆)-alkyl; or the groups R⁴ and R⁵ together with the carbon atomcarrying them form a (C₃-C₇)-cycloalkane ring which is unsubstituted orsubstituted by one or more fluorine substituents; R¹¹ and R¹⁴ areindependently of each other selected from the series consisting ofhydrogen and (C₁-C₄)-alkyl; Ar is selected from the series consisting ofphenyl, naphthyl and an aromatic, 5-membered or 6-membered, monocyclicheterocycle which comprises one or two identical or different ringheteroatoms selected from the series consisting of N, O and S, which areall unsubstituted or substituted by one or more identical or differentsubstituents selected from the series consisting of halogen,(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl and (C₁-C₄)-alkyl-O—; V is selectedfrom the series consisting of —N(R¹⁴)— and —N(R¹⁴)—(C₁-C₄)-alkyl-; and Gis selected from the series consisting of a direct bond and phenylenewhich is unsubstituted or substituted by one or more identical ordifferent substituents selected from the series consisting of halogen,(C₁-C₄)-alkyl and (C₁-C₄)-alkyl-O—, provided that G is not a direct bondif V is —N(R¹⁴), and M is R¹¹—O—C(O)—; wherein all alkyl groups areunsubstituted or substituted by one or more fluorine substituents; inany of its stereoisomeric forms or a mixture of stereoisomeric forms inany ratio, or a pharmaceutically acceptable salt thereof.
 6. A compoundof the formula I according to claim 1, selected from the seriesconsisting of:4-({2-[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionylamino}-methyl)-benzoicacid,4-({2-[1-(2-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionylamino}-methyl)-benzoicacid,4-({2-[1-(4-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionylamino}-methyl)-benzoicacid,4-{2-[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-propionylamino}-benzoicacid,4-{2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-3-methyl-butyrylaminol}-benzoicacid,4-{2-[1-(4-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-propionylamino}-benzoicacid,4-[2-(3-Naphthalen-2-yl-1-phenyl-1H-pyrazol-4-ylmethoxy)-propionylamino]-benzoicacid,4-{2-[1-(2-Chloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-propionylamino}-benzoicacid,4-[2-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethoxy)-propionylamino]-benzoicacid, 4-[2-(1,3-Diphenyl-1H-pyrazol-4-ylmethoxy)-propionylamino]-benzoicacid, 4-{2-[1-Benzyl-3-(3-methoxy-phenyl)-1H-pyrazol-4-ylmethoxy]-propionylamino}-benzoic acid,4-{2-[5-(4-Fluoro-phenoxy)-1-methyl-3-phenyl-1H-pyrazol-4-ylmethoxy]-propionylamino}-benzoicacid,4-{2-[3-(4-Cyclohexyl-phenyl)-1-phenyl-1H-pyrazol-4-ylmethoxy]-propionylamino}-benzoicacid,4-[2-(1-Phenyl-3-thiophen-2-yl-1H-pyrazol-4-ylmethoxy)-propionylamino]-benzoicacid, and4-[2-(1,5-Diphenyl-1H-pyrazol-3-ylmethoxy)-propionylamino]-benzoic acid,in any of its stereoisomeric forms or a mixture of stereoisomeric formsin any ratio, or a pharmaceutically acceptable salt thereof.
 7. Acompound of the formula I according to claim 1, wherein R¹ is selectedfrom the series consisting of (C₁-C₄)-alkyl, Ar and Ar—(C₁-C₄)-alkyl-,wherein the Ar is selected from the series consisting of phenyl,naphthyl and an aromatic, 5-membered or 6-membered, monocyclicheterocycle which comprises one or two identical or different ringheteroatoms selected from the series consisting of N, O and S, which areall unsubstituted or substituted by one or more identical or differentsubstituents selected from the series consisting of halogen,(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl and (C₁-C₄)-alkyl-O—; R² and R³ areindependently of each other selected from the series consisting ofhydrogen, (C₁-C₄)-alkyl, Ar—and Ar—O—, wherein the Ar is selected fromthe series consisting of phenyl, naphthyl and an aromatic, 5-membered or6-membered, monocyclic heterocycle which comprises one or two identicalor different ring heteroatoms selected from the series consisting of N,O and S, which are all unsubstituted or substituted by one or more(C₁-C₄)-alkyl, wherein the alkyl group is substituted by one or morefluorine substituents; R⁴ and R⁵ are independently of each otherselected from the series consisting of hydrogen and (C₁-C₆)-alkyl; and Vis selected from the series consisting of —N(R¹⁴)- and—N(R¹⁴)-(C₁-C₄)-alkyl-; in any of its stereoisomeric forms or a mixtureof stereoisomeric forms in any ratio, or a pharmaceutically acceptablesalt thereof.
 8. A compound of the formula I according to claim 7,wherein R¹ is selected from the series consisting of Ar andAr—(C₁-C₄)-alkyl-, wherein the Ar is selected from the series consistingof phenyl or naphthyl, each of which is unsubstituted or substituted byone or more identical or different substituents selected from the seriesconsisting of halogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl and(C₁-C₄)-alkyl-O—; R² and R³ are independently of each other selectedfrom the series consisting of hydrogen, (C₁-C₄)-alkyl and Ar—, whereinthe Ar is selected from the series consisting of phenyl and naphthyl,each of which is unsubstituted or substituted by one or more(C₁-C₄)-alkyl, wherein the alkyl group is substituted by one or morefluorine substituents; in any of its stereoisomeric forms or a mixtureof stereoisomeric forms in any ratio, or a pharmaceutically acceptablesalt thereof.
 9. A compound of the formula I according to claim 8,wherein R¹ is phenyl, unsubstituted or substituted by one or moreidentical or different substituents selected from the series consistingof halogen, (C₁-C₄)-alkyl, (C₃-C₇)- cycloalkyl and (C₁-C₄)-alkyl-O—; R²and R³ are independently of each other selected from the seriesconsisting of hydrogen, (C₁-C₄)-alkyl and phenyl, unsubstituted orsubstituted by one or more (C₁-C₄)-alkyl, wherein the alkyl group issubstituted by one or more fluorine substituents; in any of itsstereoisomeric forms or a mixture of stereoisomeric forms in any ratio,or a pharmaceutically acceptable salt thereof.
 10. A compound of theformula I according to claim 9, wherein R¹ is phenyl substituted by oneor more halogen; R² is hydrogen or (C₁-C₄)-alkyl; and R³ is phenylsubstituted by one or more CF₃; in any of its stereoisomeric forms or amixture of stereoisomeric forms in any ratio, or a pharmaceuticallyacceptable salt thereof.
 11. A compound of the formula I according toclaim 10, wherein R⁴ is (C₁-C₆)-alkyl; and R⁵ is hydrogen.
 12. Acompound of the formula I according to claim 10, wherein R⁴ and R⁵ areeach (C₁-C₆)-alkyl.
 13. A method for the inhibition of the LPA receptorLPAR5 or the reduction or inhibition of platelet aggregation or thrombusformation or the reduction or inhibition of activation of mast cells orthe reduction or inhibition of activation of microglial cells in amammal in need thereof, the method comprising administering the mammalan compound of formula I,

wherein R¹ is selected from the series consisting of hydrogen,(C₁-C₆)-alkyl, (C₃-C₂)-cycloalkyl, (C3-C7)-cycloalkyl-(C₁-C₄)-alkyl-, Arand Ar—(C₁-C₄)-alkyl-; R² and R³ are independently of each otherselected from the series consisting of hydrogen, halogen, (C₁-C₄)-alkyl,(C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄) -alkyl-, Ar,Ar—(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—, (C₃-C₇)-cycloalkyl-O—,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-O—, Ar—O—and Ar—(C₁-C₄)-alkyl-O—; R⁴and R⁵ are independently of each other selected from the seriesconsisting of hydrogen, fluorine and (C₁-C₆)-alkyl; or the groups R⁴ andR⁵ together with the carbon atom carrying them form a(C₃-C₇)-cycloalkane ring which is unsubstituted or substituted by one ormore identical or different substituents selected from the seriesconsisting of fluorine and (C₁-C₄)-alkyl; R¹¹, R¹², R¹³ and R¹⁴ areindependently of each other selected from the series consisting ofhydrogen and (C₁-C₄)-alkyl; Ar is selected from the series consisting ofphenyl, naphthyl and an aromatic, 5-membered or 6-membered, monocyclicheterocycle which comprises one or two identical or different ringheteroatoms selected from the series consisting of N, O and S, which areall unsubstituted or substituted by one or more identical or differentsubstituents selected from the series consisting of halogen,(C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-,cyano and (C₁-C₄)-alkyl-O—; V is selected from the series consisting ofR¹²—N(R¹³)—, and in this case G and M are not present, or V is selectedfrom the series consisting of —N(R¹⁴)—,—N(R¹⁴)—(C₁-C₄)-alkyl-, —O— and—O—(C₁-C₄)-alkyl-, in this case G is selected from the series consistingof a direct bond and phenylene which is unsubstituted or substituted byone or more identical or different substituents selected from the seriesconsisting of halogen, (C₁-C₄)-alkyl, cyano and (C₁-C₄)-alkyl-O—,provided that G is not a direct bond if V is —N(R¹⁴)—or —O—and M isselected from the series consisting of R¹¹ —O—C(O)—and R¹²—N(R¹³)—C(O)—;wherein all alkyl groups are unsubstituted or substituted by one or morefluorine substituents, and all cycloalkyl groups are unsubstituted orsubstituted by one or more identical or different substituents selectedfrom the series consisting of fluorine and (C₁-C₄)-alkyl; in any of itsstereoisomeric forms or a mixture of stereoisomeric forms in any ratio,or a pharmaceutically acceptable salt thereof.
 14. A method according toclaim 13 wherein the method is for the treatment of thromboembolicdiseases, deep vein thrombosis, venous or arterial thromboembolism,thrombophlebitis, coronary or cerebral arterial thrombosis, cerebralembolism, renal embolism, pulmonary embolism, disseminated intravascularcoagulation, cardiovascular disorders, transient ischemic attacks,strokes, acute myocardial infarction, unstable angina, chronic stableangina, peripheral vascular disease, preeclampsia/eclampsia, thromboticcytopenic purpura, inflammatory disorders, hyperalgesia, asthma,multiple sclerosis, inflammatory pain, angiogenesis, atherothrombosis,allergic responses, or restenosis.
 15. A method according to claim 13wherein the method is for the treatment of abnormal thrombus formation,acute myocardial infarction, unstable angina, thromboembolism, acutevessel closure associated with thrombolytic therapy or percutaneoustransluminal coronary angioplasty (PTCA), transient ischemic attacks,stroke, intermittent claudication, bypass grafting of the coronary orperipheral arteries, vessel luminal narrowing, restenosis post coronaryvenous angioplasty, maintenance of vascular access patency in long-termhemodialysis patients, pathologic thrombus formation occurring in theveins of the lower extremities following abdominal, knee or hip surgery,a risk of pulmonary thromboembolism, or disseminated systemicintravascular coagulatopathy occurring in vascular systems during septicshock, viral infections or cancer.
 16. A method according to claim 13wherein the method is for the treatment of inflammatory pain, asthma,angiogenesis, demyelating diseases of the central nervous system or theperipheral nervous system, multiple sclerosis, transverse myelitis,optic neuritis, Devic's disease, Guillain-Barre syndrome or chronicinflammatory demyelinating polyneuropathy.
 17. A pharmaceuticalcomposition comprising a compound of the formula I or a pharmaceuticallyacceptable salt thereof according to claim 1, and a pharmaceuticallyacceptable carrier.
 18. A method for the inhibition of the LPA receptorLPAR5 or the reduction or inhibition of platelet aggregation or thrombusformation or the reduction or inhibition of activation of mast cells orthe reduction or inhibition of activation of microglial cells in amammal in need thereof, the method comprising administering the mammalan compound according to claim tin any of its stereoisomeric forms or amixture of stereoisomeric forms in any ratio, or a pharmaceuticallyacceptable salt thereof.
 19. A method according to claim 18, wherein themethod is for the treatment of thromboembolic diseases, deep veinthrombosis, venous or arterial thromboembolism, thrombophlebitis,coronary or cerebral arterial thrombosis, cerebral embolism, renalembolism, pulmonary embolism, disseminated intravascular coagulation,cardiovascular disorders, transient ischemic attacks, strokes, acutemyocardial infarction, unstable angina, chronic stable angina,peripheral vascular disease, preeclampsia/eclampsia, thromboticcytopenic purpura, inflammatory disorders, hyperalgesia, asthma,multiple sclerosis, inflammatory pain, angiogenesis, atherothrombosis,allergic responses, restenosis, abnormal thrombus formation, acutemyocardial infarction, unstable angina, thromboembolism, acute vesselclosure associated with thrombolytic therapy or percutaneoustransluminal coronary angioplasty (PTCA), transient ischemic attacks,stroke, intermittent claudication, bypass grafting of the coronary orperipheral arteries, vessel luminal narrowing, restenosis post coronaryvenous angioplasty, maintenance of vascular access patency in long-termhemodialysis patients, pathologic thrombus formation occurring in theveins of the lower extremities following abdominal, knee or hip surgery,a risk of pulmonary thromboembolism, or disseminated systemicintravascular coagulatopathy occurring in vascular systems during septicshock, viral infections, cancer, inflammatory pain, asthma,angiogenesis, demyelating diseases of the central nervous system or theperipheral nervous system, multiple sclerosis, transverse myelitis,optic neuritis, Devic's disease, Guillain-Barre syndrome or chronicinflammatory demyelinating polyneuropathy.